The role of T cells in periodontaldisease: homeostasis andautoimmunity

ER I C A GE M M E L L, KA Z U H I S A YA M A Z A K I & GR E G O R Y J. SE Y M O U R

It is now over 30 years since the seminal paper of

Ivanyi and Lehner (106) suggested a fundamental

role for T cells in periodontal disease. It is well

established that the development of gingivitis is

identical to the development of a delayed-type

hypersensitivity reaction and that the so-called sta-

ble lesion is essentially a T-cell-mediated response.

On the other hand, numerous studies have shown

that periodontitis is predominantly a B-cell response

with T cells having an immunoregulatory role.

Recently however it has been shown that, albeit in

mice, the periodontopathic organism Porphyro-

monas gingivalis down-regulates well over a

thousand genes in CD4-positive T cells while

up-regulating only about 30 genes. The role of

autoimmunity has also been revived with the

demonstration of both anti-collagen and anti-heat-

shock protein 60-reactive T cells in the gingival tis-

sues. In addition, the so-called T regulatory or Treg

cells have been demonstrated in periodontal tissues.

These cells are thought to have a central role in the

control of autoimmunity. The question therefore

arises as to the �role� of T cells in periodontal disease.

This article will explore the concept that because P.

gingivalis is turning off T-cell genes it may be the

mechanism that enables a balance or stability to be

reached between the plaque biofilm and the host, i.e.

the �role� of T cells may be homeostatic rather than

defensive or destructive.

With respect to autoimmunity in periodontal dis-

ease the article will put forward the concept that this

is an important and normal component of chronic

inflammation. A possible scenario in this context

could be that because chronic inflammation is

defined as the simultaneous presence of destruction

and repair, as the tissue is destroyed, i.e. the collagen

is broken down by the various proteases, it must then

be removed and the amino acids must be made

available for re-use by the fibroblasts. The production

of anti-collagen antibodies could then opsonize the

broken down collagen fragments and enhance their

phagocytosis by fibroblasts, hence facilitating the

�re-cycling� process. Such a scenario would suggest

that the �role� of autoimmunity and therefore the

controlling mechanisms are an essential part of

homeostasis. Similarly, anti-heat-shock protein

reactions in chronic inflammation could be the

means of removing damaged or destroyed cells loc-

ally and again the �role� of T cells is homeostasis.

Introduction

It is well established that periodontal disease results

from the interaction of the host’s defense mecha-

nisms with microorganisms in the dental plaque

biofilm. Since the 1990s, biofilms containing com-

plexes including P. gingivalis, Fusobacterium nucle-

atum, Tannerella forsythia, and Treponema denticola

have been related to clinical measures of periodontal

disease, particularly pocket depth and bleeding on

probing (215). Notwithstanding these observations, it

has also been shown that there is a high degree of

volatility with respect to the numbers of these

organisms over time, such that it would appear that

they are more widespread in the community than

previously thought (42). Indeed, it is now recognized

that many people carry the organisms without

manifesting disease progression (42). In this context,

it is clear that most people are in balance with their

biofilm for most of the time and it is only when this

balance is disturbed that disease results. Such dis-

turbances may involve changes in the relative

amounts of the respective cytokines or may involve

14

Periodontology 2000, Vol. 43, 2007, 14–40

Printed in Singapore. All rights reserved

� 2007 The Authors.

Journal compilation � 2007 Blackwell Munksgaard

PERIODONTOLOGY 2000

changes in the controlling cytokines without changes

in their respective amounts. These changes would be

akin to moving the fulcrum either to the left or right

as shown in Fig. 1. Such shifts could occur as a result

of environmental influences leading to an oppor-

tunistic increase in the numbers of organisms, a

depression of the host’s defense mechanisms or

indeed both. The innate susceptibility of the host

therefore reflects the interplay between the bacteria,

the host’s immune system, and environmental fac-

tors (41, 199).

T cells in periodontal disease

In 1965, Brandtzaeg and Kraus (26) demonstrated the

presence of immunoglobulin-producing plasma cells

in the gingival tissues of patients with periodontal

disease. This was the first direct evidence that adap-

tive immune mechanisms play a role in the patho-

genesis of periodontal inflammation. It was not until

1970, however, that Ivanyi and Lehner (106) using

peripheral blood lymphocyte transformation assays

highlighted a role for cell-mediated immunity in

periodontal disease. Since then, immunohistological

studies have supported the concept that the response

to plaque bacteria is immunological in nature. An

experimental gingivitis study established that a

T-cell/macrophage lesion identical to a delayed

hypersensitivity reaction (178) occurs within 4–8 days

of plaque accumulation (204) and that this was syn-

onymous with the early lesion of Page and Schroeder

(171) and with the putative stable lesion (200). The

expression of human leukocyte antigen DR and DQ

by the infiltrating T cells further suggested that these

cells are activated but the lack of CD25 expression

would indicate that they are not proliferating locally

within the tissues (204). In contrast, other early

studies demonstrated that the periodontitis lesion

involved predominantly B cells and plasma cells (128,

137, 181, 198, 202, 204) as well as a decrease in the

CD4 : CD8 ratio (39, 170, 220, 234).

The study by Ivanyi and Lehner (106) was the first

to report possible suppression of cell-mediated

immunity in advanced periodontitis subjects. The

induction of lymphocyte suppression by a number

of periodontopathic bacteria including P. gingivalis,

Actinobacillus actinomycetemcomitans, Treponema

denticola, Capnocytophaga ochracea, and F. nuclea-

tum (71, 205–207, 218) was then demonstrated. In

addition, T cells extracted from periodontal diseased

tissues were reported to have a reduced ability

to respond in an autologous mixed lymphocyte

reaction (39) supporting the suggestion of a sup-

pression of cell-mediated responses in periodontitis.

Seymour et al. (203) demonstrated a lack of inter-

leukin-2 (IL-2) production by unstimulated T cells

extracted from adult periodontitis patients and

suggested this to be a reason for the failure of these

cells to undergo spontaneous proliferation (38). In

support of this study, a reduced production of IL-2

and/or IL-2 receptor (IL-2R) expression by T cells in

patients with a reduced autologous mixed lympho-

cyte reaction has been shown (116). Furthermore,

the autologous mixed lymphocyte reaction has been

reported to return to normal following periodontal

therapy (222), supporting the concept that the

suppressive effect of plaque bacteria may be

fundamental in the conversion of a stable lesion to a

progressive lesion.

In recent years, herpesviruses have been associated

with destructive periodontal disease and in this

context it is well established that these and other

enveloped viruses induce a cellular immune

response, and an increase in CD8 T cells. In addition,

Fig. 1. Diagrammatic representation of the cytokine bal-

ance in periodontal disease. Moving the fulcrum to the

right even though there is no change in the relative

amounts of cytokines, favors the formation of a progres-

sive lesion (A). Moving the fulcrum to the left again with

no change in the relative amounts of cytokines this time

favors the development of a stable lesion (B).

15

The role of T cells in periodontal disease

Epstein–Barr virus promotes the proliferation of B

cells and it has been postulated that this response to

the periodontal presence of viruses could explain the

observed immunohistological changes and predom-

inance of B cells in the progressive lesion (reviewed in

Ref. 213).

The reduced functional capacity of peripheral

blood mononuclear cells from periodontitis patients

with respect to their spontaneous proliferative

response compared with the response of cells from

healthy subjects has recently been revisited in a study

by Emingil et al. (60). However, because of the

complex etiology of periodontal disease, answers to

why periodontopathic bacteria induce their effects

have not yet been explained adequately. It is never-

theless possible to speculate that the role of T cells in

the stable lesion is one of homeostasis, i.e. of main-

taining the balance between the host and the biofilm,

and it is when the balance shifts in favor of the

suppressive effect of the bacteria that disease pro-

gression occurs.

T cells are involved in nearly all immunoregula-

tory interactions both in vivo and in vitro (184) and

a delicate balance between effector and regulatory

subsets is required for immune homeostasis (183).

The production of appropriate cytokines in re-

sponse to infection is necessary for the develop-

ment of protective immunity (76). T helper type 1

(Th1) cells increase the ability of macrophages to

kill intracellular and extracellular pathogens and

also mediate delayed-type hypersensitivity reactions

(186).

Furthermore, there is evidence that T cells are

involved in the recruitment and activation of neu-

trophils at the site of infection (31, 46). Neutrophil

activation has been shown to require direct contact

with T cells and is independent of cytokine release

(262). Therefore in the stable lesion, activation of

neutrophils may be crucial in keeping the infection

under control. It has been suggested that a strong

innate immune response in the gingival tissues

leads to the production of IL-12, which in turn

leads to a Th1 response (76). The presence of nat-

ural killer cells in gingival tissues has also been

demonstrated (255) and may be significant in the

establishment of a Th1 response. The production of

interferon-c then enhances the phagocytic activity

of both neutrophils and macrophages and hence

containment of the infection.

It is also well established that the herpesviruses

promote the expression of Th1 cytokines, such that

containment of any viral influence would also favor a

Th1 response (reviewed in Ref. 213).

In contrast, the B-cell nature of the progressive

lesion (197) suggests either an increase in the

production of Th2 cytokines or a decline in the

production of Th1 cytokines. In other words, it

suggests a shift in the balance towards Th2. Gram-

negative bacteria associated with disease progres-

sion have long been cited as being polyclonal B-cell

activators (reviewed in Refs 201 and 238), as has

Epstein–Barr virus (213). Therefore, as a result of

environmental factors causing growth of the plaque

biofilm, and hence an increase in the suppressive

effect of the bacteria, the biofilm may circumvent

the protective function of neutrophils and, con-

comitant with an increase in bacteria-derived

polyclonal B-cell activators, this may in turn lead to

the activation of B cells and their migration into

the lesion (72). Further proliferation of these B cells

could be induced by a local Epstein–Barr virus

infection (213).

Cytokine profiles in periodontaldisease

Studies over the past decade or so have supported

the hypothesis that Th1 cells are associated with the

stable lesion and Th2 cells are associated with dis-

ease progression (5, 16, 67, 72, 126, 143, 175, 182,

209, 240). However, other studies have reported a

predominance of Th1-type cells or reduced Th2 re-

sponses in diseased tissues (54, 191, 232). Recently,

the involvement of both Th1 and Th2 cells in peri-

odontal disease in humans (19, 68, 78, 113, 158, 179,

248, 257) and in a mouse model (77, 84) has been

suggested. However, while showing cytokine pat-

terns reflecting both subsets in inflamed gingival

tissues, Yamamoto et al. (257) conceded that a pre-

dominant expression of Th2 cytokines could con-

tribute to the induction of high B-cell responses in

local disease sites. Indeed, in recent years several

reports have established that Th2 responses are

associated with periodontitis. One of these studies

demonstrated that peripheral blood mononuclear

cells from patients with so-called early-onset perio-

dontitis (probably what is now recognized as

aggressive periodontitis) expressed reduced inter-

feron-c protein and decreased interferon-c and IL-2

messenger RNA in response to mitogens, indicating

reduced Th1 responses, while higher IL-5 and

granulocyte–macrophage colony-stimulating factor

were produced by cells from chronic periodontitis

patients, suggesting increased Th2 responses (209).

More significantly, an investigation of the activity of

16

Gemmell et al.

P. gingivalis cysteine proteases found that these

gingipains hydrolyzed IL-12, thereby reducing IL-12-

induced interferon-c production by CD4 cells. It was

concluded that inactivation of IL-12 by the gingi-

pains would therefore favor Th2 cells with disease

progression (261). Significantly, lower levels of IL-

12p70 produced by peripheral blood cells from per-

iodontitis patients after stimulation with Escherichia

coli lipopolysaccharide have also been reported (65).

Whether E. coli or P. gingivalis induces the same

response with respect to IL-12, or whether plaque

bacteria, in particular those associated with perio-

dontitis, down-regulate the systemic response as

found in the early studies two to three decades ago is

not certain. The results of the early studies could,

however, be explained by the down-regulation of IL-

12 and therefore of Th1 responses and hence IL-2-

mediated proliferation. Finally, the numbers of

immunoglobulin G4-positive (IgG4+) B cells in the

gingival tissues have been shown to increase relative

to IgG2+ cells with increasing inflammation, indica-

ting the influence of IL-4 and Th2 responses and

decreased interferon-c and Th1 responses in large

infiltrates in periodontal disease (86).

In 1995, a study showed that the majority of CD4

clones established from gingival tissues and raised

non-specifically using mitogen and IL-2 had Th2

phenotypes producing high levels of IL-4 and low

levels of interferon-c. However, the majority of CD8

clones produced equal amounts of IL-4 and inter-

feron-c (248). A further study demonstrated two

subsets of CD8 clones, one of which produced high

levels of interferon-c but no IL-4 or IL-5 (Th1) and

mediated cytolytic activity. The other subset pro-

duced high levels of IL-4 together with IL-5 and

displayed no cytotoxicity but could suppress the

proliferative response of cytotoxic CD8 T-cell clones.

It was concluded that CD8 T cells might participate

in the local response by suppressing interferon-c-

producing cells and favoring humoral immune

responses (249). A higher level of intracellular IL-4

produced by peripheral blood CD8 cells from highly

susceptible patients with severe periodontitis has

since been shown, further supporting a role for CD8

cells in periodontitis together with a shift towards a

type 2 function (174). However, Teng (236) recently

played down a role for CD8 cells in periodontal

disease by concluding that this subset does not par-

ticipate directly in periodontal disease destruction

during disease progression. It was suggested that

these cells not only produce important cytokines for

both innate and adaptive immune responses but

also participate in lysis of bacteria-infected or

bacteria-damaged tissues and cells. Obviously with

the increased numbers of CD8 cells relative to CD4

cells in progressive lesions, the determination of the

functions of this subset is paramount in under-

standing the pathogenesis of periodontal disease.

It is likely that different T-cell subsets predominate

at different stages of disease and the inability to

determine disease activity clinically is a major limi-

tation in all studies (168). However, it remains clear

that the balance of cytokines in inflamed periodontal

tissues is what determines whether the disease

remains stable or leads to progression and tissue

destruction (168). In this context, the control of Th1

and/or Th2 expression is fundamental to under-

standing the immunoregulatory mechanisms in

chronic periodontitis.

B cells in periodontal disease

There is no doubt that T cells play a fundamental role

in periodontal disease. They are the dominant cell

type in the cell-mediated (macrophage/lymphocyte)

response and are necessary for both specific antibody

production and polyclonal B-cell activation, which

has been cited as being significant in the pathogen-

esis of periodontal disease (20, 32, 53, 104, 141, 169).

However, polyclonal activators do not activate all B

cells. Approximately 30% of B cells may be stimula-

ted with different antigens acting on different sub-

populations. Further, the antibodies produced will

most likely be of low affinity and the memory

component may not be induced (238). While B-cell

activation in periodontitis could be the result of non-

specific polyclonal activation and/or specific induc-

tion of sensitized B cells, IgG production by gingival

cells from patients with adult periodontitis has been

shown to be reduced in comparison with peripheral

blood B cells from the same patients and this dis-

tinctiveness of the local B-cell response has been

suggested to be the result of the unique combination

of T cells in the gingival tissues of patients with

periodontal disease (135).

The inability of specific antibodies to eliminate the

causative organisms of periodontal disease could be

the result of a number of factors, including poor

antigenicity of the virulence determinants and elici-

tation of antibodies with poor anti-bacterial proper-

ties (212). High titers of specific antibodies to

P. gingivalis (147, 254) and A. actinomycetemcomitans

(63, 129, 147, 190) have been demonstrated in the

serum and gingival crevicular fluid of periodontal

disease subjects, although the reports with respect to

17

The role of T cells in periodontal disease

disease activity are conflicting (15, 56, 157). Studies

on immunodominant antigens of P. gingivalis (43,

124, 176) and A. actinomycetemcomitans (29, 30, 57,

62) have also shown different patterns of immuno-

reactivity. The production of anti-P. gingivalis anti-

bodies with different avidities in various forms of

periodontal disease has been suggested to reflect the

quality of the humoral response, which may affect

progression of the disease (153). Anti-A. actinomyce-

temcomitans (242) and anti-P. gingivalis antibodies

(154) with higher avidities have been suggested to

confer greater resistance to continued or repeated

infection. Non-protective low avidity anti-P. gingi-

valis antibodies may be incapable of effectively

mediating a variety of immune responses (131, 251).

During the chronic phase of the disease, the

antibody response has been suggested to be gener-

ally protective, facilitating bacterial clearance and

arresting disease progression (166). An increased

capacity of serum to opsonize P. gingivalis has been

shown to be a distinctive feature in patients with

past destructive periodontal disease (254). This may

be because of the ability of anti-P. gingivalis prote-

ase antibodies, which occur late in periodontitis

infections, to block the anti-opsonizing activity

against C3 and IgG (45). Opsonic IgG antibodies to

A. actinomycetemcomitans, which may facilitate

neutrophil-mediated phagocytosis and be protective

against this periodontopathic organism, have also

been demonstrated (13, 242). Repeated infection

with A. actinomycetemcomitans has been shown to

elicit an anti-leukotoxin antibody that protects

neutrophils from the leukocidal activity of the leu-

kotoxin (242).

Therefore, if specific antibodies with high avidity

and protective IgG subclasses to immunodominant

antigens are formed, the infection may be cleared

and the disease will not progress. However, poly-

clonal B-cell activation by periodontopathic bacteria

and the production of non-specific and/or

low-avidity specific antibodies may not clear the

infection. Continued B-cell activation leads to the

production of high levels of IL-1 resulting in tissue

destruction. Dendritic cells may provide signals that

initially activate T cells, while B-cell presentation may

allow for further activation and clonal expansion of

these already activated cells. An allogeneic mixed

leukocyte reaction was used to show that activated B

cells could act as potent antigen-presenting cells in

the presence of P. gingivalis or A. actinomycetem-

comitans, resulting in the production of high levels of

interferon-c and minimal IL-5 (139). Although other

cytokines such as IL-4 were not measured in this

study, there is evidence that B cells direct Th2 CD4+ T

cells whereas macrophages activate Th1 cells (re-

viewed in Ref. 22) providing support for the concept

of antigen-specific T-cell and B-cell activation lead-

ing to Th2 responses in the B-cell periodontitis

lesion.

Inhibition of innate immunity inperiodontitis

In the gingival sulcus, neutrophils form a barrier

between the epithelium and the plaque biofilm (9),

which in most cases prevents bacterial invasion of

the epithelium and underlying connective tissue (96).

Both P. gingivalis and A. actinomycetemcomitans

have been reported to be capable of invading epi-

thelial cells and even the connective tissues in dis-

eased sites (64, 125, 192). Significantly, P. gingivalis

has been shown to have direct effects on the host

innate immune responses (reviewed in Ref. 48). The

migration of neutrophils from the circulation into the

tissues has been shown to be inhibited by suppres-

sing the expression of the neutrophil-binding adhe-

sion molecule E-selectin on endothelial cells (47) and

by blocking neutrophil transmigration through oral

epithelium by inhibiting the epithelial cell produc-

tion of the chemokine IL-8 (138). A mouse model also

demonstrated inhibition of neutrophil phagocytosis

of immune serum-opsonized P. gingivalis (85),

possibly as a result of the cleavage of complement

and immunoglobulins by the P. gingivalis proteases

that prevent opsonization and subsequent neutrophil

killing of the bacteria (133, 193, 194, 221). A. actino-

mycetemcomitans produces a protein that inhibits

neutrophil chemotaxis and hydrogen peroxide pro-

duction (7, 8) as well as a cytolytic leukotoxin which

lyses susceptible target cells including neutrophils,

monocytes and T cells (142, 227, 228). Interestingly,

unlike P. gingivalis and A. actinomycetemcomitans,

a recent mouse model study demonstrated that

T. forsythia, which is also implicated in periodontal

disease progression, did not affect neutrophil

migration into T. forsythia-induced lesions (89) and

therefore may not inhibit innate immune responses.

Macrophages too may be targeted for inhibition

by P. gingivalis. P. gingivalis has been reported to

stimulate the production of IL-1b by B cells rather

than monocytes and, as discussed below, to affect

macrophage migration by inhibiting the production

of one of the major monocyte/macrophage chem-

okines, monocyte chemoattractant protein-1 (79,

80).

18

Gemmell et al.

T-cell suppression in periodontitis

Cytokines

We have recently used microarray analysis to show

that in BALB/c mice, P. gingivalis has a powerful

down-regulatory effect on splenic CD4 and CD8 cells.

Only five and 28 genes respectively were up-regulated

in the two subpopulations and in contrast, close to

1200 genes were down-regulated in each subset.

P. gingivalis had separate effects on the two

sub-populations with overlap being limited to 20%.

While most of the down-regulated genes were con-

cerned with metabolism, some coded for immune

response proteins. These included several chemo-

kine-like factors, chemokine ligands, and chemokine

receptors, suggesting interference with the recruit-

ment of selected leukocytes or their binding (Table 1,

Ref. 87). As stated above, P. gingivalis inhibits macr-

ophage migration in humans by inhibiting the pro-

duction of monocyte chemoattractant protein-1 (79).

Furthermore, decreased levels of the neutrophil

chemoattractant IL-8 and monocyte chemoattractant

protein-1 have been demonstrated in umbilical vein

endothelial cells challenged with P. gingivalis (118).

These studies are in contrast to a recent report that

found a more frequent and higher expression of

monocyte chemoattractant protein-1 and its receptor

CCR4 in gingival biopsies taken from patients with

chronic periodontitis, although these findings were

relative to biopsies from patients with aggressive

periodontitis (69) not to control healthy or gingivitis

tissue sections. However, P. gingivalis gene expres-

sion for colony-stimulating factor 1 receptor, which

regulates the proliferation and differentiation of

monocyte/macrophage precursors (252), was also

down-regulated (87). Stimulatory DNA including

lipopolysaccharide has been shown to stop the

growth of murine marrow-derived macrophages

proliferating in colony-stimulating factor 1 by down-

modulating surface colony-stimulating factor 1

receptor expression (196). No increase in macroph-

age numbers and little evidence of macrophage

activation have been demonstrated in advanced

periodontitis compared with minimally inflamed

tissues (35), suggesting that macrophages may have

protective effects in the stable lesion which are

abrogated in the advanced destructive lesion by

P. gingivalis.

Another gene down-regulated by P. gingivalis

codes for the cytokine receptor IL-17R (87). IL-17R-

deficient mice have a defect or display a significant

delay in neutrophil recruitment into infected sites

resulting in susceptibility to infection (114), which

may account partly for the reported inhibition of

neutrophils in the P. gingivalis-induced lesion in

mice (75). In contrast to the study in mice, IL-17

expression has been shown to be up-regulated in

human periodontitis tissue (165). This finding was

supported by the gene expression profile of T-cell

clones established from periodontitis patients where

51% of gingival T-cell clones expressed IL-17 com-

pared with only 11% of peripheral blood T-cell clones

(105). In addition, stimulation of peripheral blood

mononuclear cells by P. gingivalis antigen enhanced

not only transcription but also translation of the

IL-17 gene (165). As IL-17 is capable not only of

inducing IL-6 in gingival fibroblasts but also of

enhancing the humoral immune response as well as

the inflammatory response, the balance between the

production of IL-17 and expression of its receptor

further reflects the fact that cytokines cannot be

studied in isolation and that it is the balance of

cytokines that is fundamental in disease expression.

Further genes down-regulated in the microarray

study included those which code for myeloperoxi-

dase, peptidoglycan recognition protein, CD14, toll-

like receptor 1 (TLR1) and toll interacting protein

(87). Myeloperoxidase is produced by macrophages

and neutrophils and participates in the respiratory

antimicrobial defense system (151). Peptidoglycan

recognition proteins, which are also critical for innate

immune responses, bind peptidoglycan in bacterial

cell walls and are involved in the killing and degra-

dation of cell wall components and the initiation of

host defense reactions (144). CD14 is expressed

mainly by macrophages and plays a central role in

innate immunity as a receptor for bacterial lipo-

polysaccharide (61). Lipopolysaccharide also stimu-

lates the innate immune response through TLR4.

TLR1 has been found to be physically associated with

TLR4 and has been demonstrated to have the capa-

city to abrogate TLR4 signaling and thus prevent in-

nate responses to lipopolysaccharide (217). TLR1 has

also been shown to associate with TLR2 to recognize

native mycobacterial lipoprotein as well as other

lipopeptides (233). A recent study reported that

the Th1 cytokines interferon-c and granulocyte–

macrophage colony-stimulating factor enhanced

TLR1 expression while the Th2 cytokine IL-4 down-

regulated TLR2 expression in monocytes and dend-

ritic cells (123). Furthermore, toll-interacting protein

has been demonstrated to co-immunoprecipitate

with TLR2 and TLR4 and may be an important con-

stituent of both the TLR2 and TLR4 signaling path-

ways (28). Overall, these results support other data

19

The role of T cells in periodontal disease

Table 1. Gene expression changes in Porphyromonas gingivalis-activated CD4 and CD8 cells

Gene title Gene symbol CD4› CD8› CD4fl CD8fl

Cytokines, chemokines, related factors, cytokine receptors

Chemokine-like factor Cklf ) ) ) +

Chemokine-like factor super family 3 Cklfsf3 ) ) + )

Chemokine-like factor super family 7 Cklfsf7 ) ) + +

Chemokine (C-C motif) ligand 2 Ccl2 ) ) ) +

Chemokine (C-C motif) ligand 9 Ccl9 ) ) ) +

Chemokine (C motif) receptor 1 Xcr1 ) ) ) +

Chemokine (C-C motif) receptor 2 Ccr2 ) ) ) +

Chemokine (C-C motif) receptor 3 Ccr3 ) ) + )

Chemokine (C-X-C motif) receptor 6 Cxcr6 ) ) + )

Colony-stimulating factor 1 receptor Csf1 ) ) + )

Colony-stimulating factor 2 receptor, a, low-affinity

(granulocyte-macrophage)

Csf2ra ) ) + +

Interferon-c receptor 2 Ifngr2 ) ) ) +

Interleukin-1b Il1b ) ) + )

Interleukin 1 family, member 9 Il1f9 ) ) ) +

Interleukin-1 receptor-associated kinase 4 Irak4 ) ) + )

Interleukin 2 receptor c chain Il2rg ) ) ) +

Interleukin 6 receptor a Il6ra ) ) + )

Interleukin 6 signal transducer Il6st ) ) ) +

Interleukin 7 receptor Il7r ) ) ) +

Interleukin 10 receptor b Il10rb ) ) + )

Interleukin 16 Il16 ) ) ) +

Interleukin 17 receptor Il17r ) ) + +

Interleukin 17 receptor B Il17rb ) ) + )

Interleukin 18 Il18 ) ) + )

Interleukin 18 receptor accessory protein Il18rap ) ) ) +

Transforming growth factor b1 Tgfb1 ) ) + +

Transforming growth factor b-induced Tgfbi ) ) + )

Transforming growth factor b receptor II Tgfbr2 ) ) ) +

Ig binding/B-cell immunity

CD19 antigen Cd19 ) ) ) +

CD22 antigen Cd22 ) ) ) +

CD79A antigen (immunoglobulin-associated a) Cd79a ) ) + +

CD79B antigen Cd79b ) ) + +

Fc receptor, IgE, high affinity I, c polypeptide Fcer1g ) ) + )

Fc receptor, IgE, low affinity II, a polypeptide Fcer2a ) ) ) +

Fc receptor, IgG, high affinity I Fcgr1 ) ) + )

20

Gemmell et al.

Table 1. Continued

Gene title Gene symbol CD4› CD8› CD4fl CD8fl

Fc receptor, IgG, low affinity Iib Fcgr2b ) ) + +

Fc receptor, IgG, low affinity III Fcgr3 ) ) + +

Similar to immunoglobulin c-2a heavy chain Igh-1a + ) ) )

Immunoglobulin heavy chain 4 (serum IgG1) Igh-4 + ) ) )

Immunoglobulin heavy chain 6 (heavy chain of IgM) Igh-6 ) ) + +

Immunoglobulin heavy chain (gamma polypeptide) Ighg ) ) ) +

Immunoglobulin j chain variable 21 (V21) /// Anti-c-erbB-2/

p185 monoclonal antibody SER4 heavy chain variable region

Igk-V1 ) ) ) +

Immunoglobulin kappa chain variable 32 (V32) Igk-V32 ) ) ) +

immunoglobulin lambda chain, variable 1 Igl-V1 ) ) ) +

T cell immunity

CD2 antigen (cytoplasmic tail) binding protein 2 Cd2bp2 ) ) ) +

CD3 antigen, f polypeptide Cd3z ) ) ) +

CD8 antigen, a chain Cd8a ) ) + +

CD8 antigen, b chain 1 Cd8b1 ) ) + +

T-cell receptor b, variable 13 Tcrb-V13 ) ) ) +

T-cell receptor b, variable 13 /// Similar to TCRBV7S1 Tcrb-V13 ) ) + +

T-cell receptor b, variable 13 /// T-cell receptor b,

joining region

Tcrb-V13 ///

Tcrb-J

) ) ) +

T-cell receptor c, variable 4 Tcrg-V4 ) ) + +

Antigen presentation/major histocompatibility complex

b2-microglobulin B2m ) ) ) +

CD1d1 antigen Cd1d1 ) ) + )

CD86 antigen Cd86 ) ) + )

ICOS ligand Icos ) ) ) +

Histocompatibility 2, class II antigen A, a H2-Aa ) ) + )

Histocompatibility 2, class II antigen A, b1 H2-Ab1 ) ) + +

Histocompatibility 2, class II antigen E a H2-Ea ) ) + )

Histocompatibility 2, class II antigen E b H2-Eb1 ) ) + )

Histocompatibility 2, class II, locus DMa H2-DMa ) ) + )

Histocompatibility 2, class II, locus Mb1 ///

histocompatibility 2, class II, locus Mb2

H2-DMb1 ///

H2-DMb2

) ) + +

Histocompatibility 2, class II, locus Mb2 H2-DMb2 ) ) + +

Histocompatibility 2, O region a locus H2-Oa ) ) + )

Histocompatibility 28 H28 ) ) + )

Human leukocyte antigen-B associated transcript 8 Bat8 ) ) + +

Ia-associated invariant chain Ii ) ) + )

Histocompatibility 2, T region locus 23 ///

RIKEN cDNA C920025E04 gene

H2-T23 ///

C920025E04Rik

) ) ) +

histocompatibility 2, T region locus 24 H2-T24 ) ) ) +

21

The role of T cells in periodontal disease

Table 1. Continued

Gene title Gene symbol CD4› CD8› CD4fl CD8fl

Innate immunity

Complement component 1, q subcomponent

binding protein

C1qbp ) ) + )

Complement component 1, q subcomponent,

a polypeptide

C1qa ) ) + )

Complement component 1, q subcomponent,

b polypeptide

C1qb ) ) + +

Complement component 1, q subcomponent,

c polypeptide

C1qg ) ) + )

Complement component 3 C3 ) ) + )

Complement component 5, receptor 1 C5r1 ) ) ) +

Complement component 6 C6 ) ) + )

CD14 antigen Cd14 ) ) + )

Myeloperoxidase Mpo ) ) + )

Peptidoglycan recognition protein 1 Pglyrp1 ) ) + )

Toll interacting protein Tollip ) ) ) +

Toll-like receptor 1 Tlr1 ) ) ) +

Extracellular matrix and cell adhesion molecules

a disintegrin and metalloprotease domain 8 Adam8 ) ) + )

a disintegrin and metalloprotease domain 10 Adam10 ) ) ) +

a disintegrin and metalloproteinase domain 17 Adam17 ) ) ) +

a disintegrin and metalloproteinase domain 19 (meltrin b) Adam19 ) ) ) +

Integrin a4 Itga4 ) ) ) +

Integrin a6 Itga6 ) ) + +

Integrin aL Itgal ) ) ) +

Integrin aM Itgam ) ) ) +

Integrin aV Itgav ) ) + )

Integrin aX Itgax ) ) + )

Integrin b2 Itgb2 ) ) ) +

Integrin b2-like Itgb2l ) ) ) +

Integrin b4 binding protein Itgb4bp ) ) ) +

Matrix metalloproteinase 9 Mmp9 ) ) + )

Procollagen, type III, a1 Col3a1 ) ) + )

Procollagen, type XIV, a1 Col14a1 ) ) + )

Syndecan 3 Sdc3 ) ) + )

Tissue inhibitor of metalloproteinase 2 Timp2 ) ) + )

Intercellular adhesion molecule 2 Icam2 ) ) ) +

Platelet/endothelial cell adhesion molecule 1 Pecam1 ) ) ) +

Selectin, lymphocyte (l-selectin) Sell ) ) ) +

22

Gemmell et al.

demonstrating that P. gingivalis evades host innate

immune responses.

P. gingivalis also down-regulated a number of

genes encoding cytokines or cytokine receptors in T

cells (87). These included the genes for IL-1b, IL-1

family 9 and IL-1R-associated kinase 4 (IRAK-4). IL-1

is a principal mediator of inflammatory responses

acting on many cell types and is itself produced by

many different cells, including macrophages, endo-

thelial cells, B cells, fibroblasts, epithelial cells,

astrocytes, and osteoblasts in response to micro-

organisms, bacterial toxins, complement compo-

nents or tissue injury (52). One of the most important

actions of IL-1 is its induction of other cytokines

(164). IL-1 is the most potent known inducer of bone

demineralization (219) as well as of major changes in

the connective tissue matrix (180). However, while

P. gingivalis depressed the gene for IL-1b in T cells,

it has, as stated above, been shown to induce an

increased percentage of peripheral blood B cells from

periodontitis patients to produce IL-1b compared

with macrophages (73). Since macrophages are not a

dominant feature of the advanced lesion (35) and

suppressed cell-mediated immunity is associated

with advanced periodontitis (25, 106), B cells may be

the major source of IL-1 in periodontitis.

One of the major effects noted in the microarray

study apart from suppression of T-cell function, was

the shift away from Th1 responses (87). IRAK is

recruited to the IL-1R complex on IL-1 stimulation

and is required for optimal transduction of IL-1-in-

duced signals (136). However, more interestingly,

interferon-c production and Th1 cell proliferation

have been shown to be severely impaired in IRAK-4-

deficient mice (223). P. gingivalis also down-regula-

ted the gene coding for interferon-c receptor 2 in CD8

cells. T cells in mice that are deficient in this receptor

were found to have a defect in Th1 differentiation

leading to lower amounts of interferon-c in response

to antigen challenge, with an alteration in interferon-

c-induced immunoglobulin class switching in B cells

(134). A study on the effect of tobacco smoke on

human peripheral blood cells by microarray analysis

found a significant depression in the gene for inter-

feron-c receptor 2 as well as that for chemokine

receptor 2 (188), so that a subject with P. gingivalis-

induced periodontitis who was also a smoker may

well have reduced interferon-c responses.

Two other genes down-regulated by P. gingivalis

included IL-18 and IL-18R accessory protein

(IL-18Rap) (87). IL-18 is a member of the IL-1 family

(90) and the IL-18Rap is required for IL-18 signaling

(24). IL-18 can act with IL-12 to promote the genera-

tion of interferon-c-producing Th1 cells (160),

suggesting again that P. gingivalis promotes the

down-regulation of this T-cell subset. However,

another study reported higher concentrations of IL-18

in gingival biopsies from sites with a probing depth

>6 mm compared with healthy sites although IL-12

concentrations were significantly lower (108). This

combination would also lead to reduced Th1

responses. Yet another study reported a higher pro-

duction of IL-18 by whole blood cells from patients

with periodontitis although the stimulus was E. coli

lipopolysaccharide (65). Although this study also

showed reduced IL-1b in response to E. coli, the lipo-

polysaccharides from this bacterium and from

P. gingivalis appear to have differential effects.

The gene coding for the IL-10Rb was down-regu-

lated by P. gingivalis in CD4 cells (87), suggesting an

inability of these cells to respond to IL-10. IL-10 has

many biological functions including the limitation

Table 1. Continued

Gene title Gene symbol CD4› CD8› CD4fl CD8fl

Selectin, platelet (p-selectin) ligand Selpl ) ) + +

Vascular cell adhesion molecule 1 Vcam1 ) ) + +

Bone metabolism

Osteoclast stimulating factor 1 Ostf1 ) ) + )

Wound healing

Elastase 1, pancreatic Ela1 ) + ) )

Elastase 2 Ela2 ) + ) )

Elastase 3B, pancreatic Ela3b ) + ) )

Reproduced from Gemmell et al. (87).

23

The role of T cells in periodontal disease

and termination of inflammatory responses and

regulation of proliferation and differentiation of

immunocompetent cells, including T and B cells and

antigen-presenting cells (reviewed in Ref. 6). The non-

responsiveness of T cells to P. gingivalis has recently

been shown, although peripheral blood B cells did

proliferate and high levels of IL-10 were produced by

monocytes. IL-10 itself could induce B-cell prolifer-

ation and it was suggested that P. gingivalis may play

a role in polyclonal B-cell activation associated with

periodontal disease via a macrophage-dependent

IL-10 route (34). However, as previously stated,

macrophages are most likely not activated in

periodontitis lesions (35), suggesting the possible

importance of the lack of this immunosuppressive

cytokine in periodontitis lesions. However, one of the

important effects of IL-10 is its direct inhibitory

effects on interferon-c production (49) and in

humans, IL-10 promotes Th2 responses while sup-

pressing delayed-type hypersensitivity reactions and

other Th1-cell-mediated responses (103). While the

microarray study indicated that CD4 cells would not

respond to IL-10 because of the down-regulation of

the IL-10Rb gene, the down-regulation of the other

genes, including IRAK-4, interferon-c receptor 2, IL-

18 and IL-18Rap, would still suggest a swing away

from Th1 responses.

The microarray study also demonstrated the down-

regulation by P. gingivalis of the gene encoding the

IL-2Rc chain in CD8 cells (87). The IL-2Rc is shared

by receptor complexes used by IL-2 and other

cytokines including IL-4, IL-7, IL-9 and IL-15, all of

which are involved in lymphocyte development and/

or activation. IL-2Rc is physically associated with

JAK3 tyrosine kinase (which was also down-regulated

in CD4 cells), and this molecular pair may be con-

sidered to be the trigger of the signaling cascades.

X-linked severe combined immunodeficiency in

humans is caused by mutations in the IL-2Rc gene

that result in absent T cells and non-functional B cells

(10). Prevotella intermedia strains have been shown

to not only inhibit T-cell and B-cell proliferation in

response to mitogens and antigens, but to inhibit

IL-2R expression on T cells (208). The down-regula-

tion of the IL-2Rc chain may well support studies

demonstrating a lack of IL-2 production and reduced

IL-2R expression by T cells in patients with a reduced

autologous mixed lymphocyte reaction (116, 203).

P. gingivalis also induced the down-regulation of

the genes coding for transforming growth factor-b1

and the transforming growth factor-b2 receptor (87).

Transforming growth factor-b is a pleiotropic cyto-

kine with transforming growth factor-b receptors

being expressed on most cell types (88); down-regu-

lation of the cytokine and its receptor would have

wide-ranging effects (87). A mouse model in which

transforming growth factor-b was blocked specifically

in T cells, demonstrated that T-cell homeostasis re-

quires transforming growth factor-b signaling (88).

Hence, the ability of P. gingivalis to down-regulate

the genes coding for this cytokine further illustrates

the dynamic balance that may be occurring between

the plaque biofilm and the host.

Another study in mice showed that transforming

growth factor-b is important for B-cell development

and that B-cell progenitors are differentially affected

according to their stage of differentiation (112).

Transforming growth factor-b is also involved in all

aspects of wound healing entailing inflammation,

re-epithelialization, matrix formation, and remode-

ling (3). It is produced locally at the site of resorption

of bone and has been shown to initiate new bone

formation (33). The down-regulation of transforming

growth factor-b in T cells confirms an earlier study

which demonstrated that more transforming growth

factor-b may have been produced by peripheral

blood mononuclear cells in culture in the absence of

stimulatory bacteria (72).

Surface membrane antigens

As well as down-regulating a number of cytokine-

related genes, P. gingivalis also down-regulated

several genes encoding proteins which directly affect

T-cell function (87). These included CD2-binding

protein 2 expression. This protein binds to a site

within the cytoplasmic region of CD2 and over-

expression of the isolated protein enhances IL-2

production on cross-linking of CD2 in Jurkat T cells

(163). The cell adhesion molecule CD2 is expressed

by T cells and recognized by CD48 in mice and CD58

(lymphocyte function-associated antigen-3; LFA-3) in

humans (253). CD2–CD48 interactions have been

shown to be critical for the production of sufficient

IL-2 and interferon-c to induce the differentiation of

CD8+ cells into functional cytotoxic cells (155). The

CD2 molecule is expressed on the majority of murine

lymphocytes and plays a regulatory role in antigen-

specific responses via the T-cell receptor (167, 243).

The absence of CD2 on murine T-cell receptor a/b+ T

cells has been shown to co-segregate with non-

responsiveness (243). CD2+ T cells have been dem-

onstrated in the gingival tissues of patients with

chronic periodontitis (91) although a lower percent-

age of positive cells has been reported compared with

peripheral blood T cells (74). Taken together, these

24

Gemmell et al.

results suggest an increase in non-responsive T cells

in the gingival tissues as a result of the down-regu-

lation of the CD2 binding protein 2 by P. gingivalis in

periodontitis. Yet again, they also indicate a swing

away from the Th1 cytokines IL-2 and interferon-c.

The T-cell receptor is a complex composed of the

antigen-binding heterodimer (a/b or c/d chains) and

a signal transducing complex consisting of the CD3

dimers (CD3 c/e and CD3 d/e) and the T-cell receptor

f homodimer (95). This T-cell receptor–CD3 complex

plays a key role in antigen recognition, T-cell acti-

vation, and triggering antigen-specific responses (23).

The microarray study demonstrated that the gene

coding for CD3f was down-regulated by P. gingivalis

(87). T cells from patients with systemic lupus

erythematosus display T-cell receptor f chain aber-

rations as well as defective IL-2 production (162),

suggesting another association between reduced IL-2

production and P. gingivalis-induced periodontitis.

The cell surface glycoprotein CD8 functions as a

co-receptor with the T-cell receptor for interaction

with major histocompatibility complex class I mole-

cules (50) CD8 exists as homodimers of a polypeptide

chains and heterodimers of a and b chains and while

the CD8a chain binds to major histocompatibility

complex class I, the function of CD8b, for which there

are two genes, CD8b1 and CD8b2, is not as clear (51,

161). Gemmell et al. (87) demonstrated down-regu-

lation of the genes for CD8a and b1 chains in both

CD4 and CD8 cells. It has recently been shown that

CD8 is expressed on CD4 cells in rats and these cells

helped in primary humoral responses and produced

mainly Th1 cytokines (115). Therefore, it follows that

in periodontitis, Th1 cytokines produced by helper T

cells expressing CD8 may be decreased. However, a

down-regulation of CD8 responses induced by P.

gingivalis is at odds with reports showing a decrease

in the CD4 : CD8 ratio in periodontitis biopsies

compared with peripheral blood and healthy/gingi-

vitis tissue (170, 234).

Cell adhesion molecules

Leukocytes migrate into the tissues from the peri-

pheral circulation and the first step in this migration

is binding to endothelial cell adhesion molecules.

These endothelial cell adhesion molecules are

expressed on endothelial cells as well as on leuko-

cytes and a recent report showed that while LFA-1/

endothelial cell adhesion molecule-1 binding resul-

ted in the production of IL-10, LFA-1/endothelial cell

adhesion molecule-2 binding induced a stronger

secretion of the Th1 cytokine tumor necrosis factor-a

(21). Adhesion molecules are therefore important

factors in determining the homing of leukocyte sub-

sets as well as imparting other functional roles such

as differential cytokine production. The genes enco-

ding endothelial cell adhesion molecule-2 and several

integrins were down-regulated in mice by P. gingi-

valis, particularly in the CD8 cells (87). Integrins

mediate the migration of leukocytes through the

extracellular matrix and induce signals that direct

different cellular signaling pathways (44). Interest-

ingly, the b2 integrin subunit of LFA-1 (CD18) was

down-regulated in CD8 cells, which would result in

the abrogation of the LFA-1/endothelial cell adhesion

molecule-2 pathway. Overall these results may indi-

cate a role for P. gingivalis in down-regulating Th2

cytokines.

Antigen presentation

As already stated, P. gingivalis and A. actinomyce-

temcomitans are capable of invading epithelial cells

(64, 192). Keratinocytes expressing class II molecules

have been reported in inflamed sites of gingival tis-

sues (204), suggesting that in humans, gingival kera-

tinocytes can present antigens to the underlying

lymphocytes (189). An animal model has only

recently shown that rat gingival epithelial cells trea-

ted with interferon-c and A. actinomycetemcomitans

express major histocompatibility complex class II

molecules and the co-stimulatory molecule CD80

and can stimulate A. actinomycetemcomitans-specific

CD4 cells to proliferate (145). However, it is also

possible that Langerhans cells in the gingival epi-

thelium (82, 109) may also present P. gingivalis

antigens. Furthermore, different dendritic cell sub-

sets have been demonstrated in the gingival tissues

and have been shown to associate with clusters of

CD4 cells, suggesting that antigen presentation to T

cells may occur in the connective tissues (109). While

peptide antigens are recognized in an major

histocompatibility complex-restricted manner, lipid-

containing antigens such as lipoprotein and lipo-

polysaccharide are recognized in a CD1-restricted

manner. Cells expressing all isoforms of CD1, namely

CD1a, b, c, and d, are present in periodontitis tissue

and the total expression of CD1 is equivalent to that

of CD83, a marker of mature dendritic cells. This

suggests the potential importance of lipid antigens in

chronic periodontitis (2).

It is however, becoming apparent that T cells

themselves can present antigen. Resting cattle CD4

cells from calves immunized with ovalbumin or res-

piratory syncytial virus were found to proliferate in

25

The role of T cells in periodontal disease

response to c/d T cells pulsed with antigen-present-

ing cells expressing high levels of major histocom-

patibility complex class II molecules and synthesizing

the co-stimulatory molecule CD80 (40). Another

study showed similar results using circulating

porcine c/d T cells. Peripheral blood from ovalbu-

min-immunized pigs depleted of all conventional

antigen-presenting cells were able to proliferate in

response to antigen and this response was abolished

after depletion of c/d T cells and anti-major histo-

compatibility complex class II or anti-CD4 antibodies

(230). An earlier study in humans demonstrated that

tetanus antigen-specific T-cell clones pre-incubated

with antigen followed by irradiation could present

antigen and initiate proliferation by autologous

cloned T cells. Again this antigen presentation was

abrogated by treatment with anti-human leukocyte

antigen-DR or anti-tetanus antibodies. Autologous

peripheral blood resting T cells or phytohemaggluti-

nin-activated T-cell blasts could not present antigen

to responder cloned T cells (37). More recently, it has

been reported that human T cells can acquire large

quantities of major histocompatibility complex class

II molecules from various types of antigen-presenting

cells in an antigen-independent manner and this

required direct cell-to-cell contact and interaction of

adhesion molecules. The newly acquired major his-

tocompatibility complex class II molecules were

capable of presenting antigen to T helper cells, sug-

gesting that T cells interact with other T cells to

regulate immune responses by presenting major

histocompatibility complex class II peptide com-

plexes obtained from nearby antigen-presenting cells

(241). A further study showed that lamina propria T

cells from actively inflamed inflammatory bowel

disease mucosa expressed large amounts of major

histocompatibility complex class II molecules and

CD86 and could stimulate allogeneic naive peripheral

blood T-cell proliferation. This process was reduced

by the addition of IL-10. It was suggested that this

interaction between T cells could contribute to the

perpetuation of inflammation (59).

The study by Gemmell et al. (87) showed that

mRNA for certain class I and II molecules and the

Ia-associated invariant chain were down-regulated in

both CD4 and CD8 cells. The H-2 major histocom-

patibility complex of mice encodes two functional

proteins, Aa Ab (A) and Ea Eb (E) (226). Efficient

loading of class II molecules with peptides requires

the invariant chain and the class II-like molecule

H2-M (now H2-DM) (122). Cells from mice devoid

of the invariant chain show aberrant transport of

major histocompatibility complex class II molecules,

leading to reduced levels of class II complexes at the

surface which do not have the typical compact con-

formation indicative of tight peptide binding (246).

Because of the physical association of H2-O with

H2-M and the co-localization in class II+ vesicles, it

has been suggested that H2-O may have a related

function in peptide exchange (173). Generally, down-

regulation of these genes would lead to impairment

of antigen presentation functions. However, the

extent of T-cell–T-cell interaction in the gingival

tissues is at this stage unclear.

The suggestion of impairment of antigen presen-

tation functions in P. gingivalis-induced periodontitis

was also reflected in the down-regulation of the

genes for CD86 (a ligand of the major co-stimulatory

CD28) and inducible co-stimulatory molecule ligand

(a member of the CD28 family). Activation of T cells

leading to cytokine production requires a signal

transduced through the T-cell receptor as well as a

second signal transduced by a co-stimulatory mole-

cule (70). CD28 is the major co-stimulatory signal

receptor for T cells and its natural ligands are CD80

(B7-1) and CD86 (B7-2), which are expressed either

constitutively or after activation on antigen-present-

ing cells (1). Inducible co-stimulatory molecule, a

member of the CD28 family, is expressed by activated

T cells and binds with its ligand, which is constitu-

tively expressed on B cells. Interaction leads to

differentiation of B cells to plasma cells (127), sug-

gesting that antigen-specific activation of B cells in

periodontitis may be suppressed by P. gingivalis.

Activated monocytes, B cells and dendritic cells

express B7 molecules (111). Macrophages constitu-

tively express low levels of CD86, CD80 being

induced after treatment with interferon-c. CD86

expression is also low on B cells until activation,

which induces a rapid up-regulation of these mole-

cules (107). The percentage of CD86+ B cells and

macrophages has been shown to be significantly

higher than the percentage of CD80+ macrophages in

gingival tissue sections (81). Another study showed

that CD86 was up-regulated mostly on B cells isola-

ted from periodontitis lesions and that a number of

periodontopathic bacteria including P. gingivalis

up-regulated CD86 on B cells in vitro (139).

It is now becoming clear that T cells also express

co-stimulatory molecules. Activated human periph-

eral blood T cells, CD4 and CD8 clones and natural

killer clones have been shown to express B7 mole-

cules (11). Anti-CD28 antibodies or CTLA4-Ig fusion

protein have been demonstrated to inhibit the

proliferation of specific T-cell clones in response

to T cells acting as antigen-presenting cells or

26

Gemmell et al.

proliferation of peripheral blood mononuclear cells

in a primary allostimulation with activated T cells as

stimulator cells. B7 was also found to be expressed on

subsets of freshly isolated activated CD4 or CD8 cells

from some individuals infected with human immu-

nodeficiency virus or from others with autoimmune

diseases, although T cells from healthy individuals

did not express B7 (256). Hirokawa et al. (98)

suggested that B7 molecules functioned as co-stim-

ulatory molecules on T cells and played a role in

interactions between T cells leading to clonal

expansion of activated T cells. Another study has

shown that memory CD4 cells express CD86 while

naive CD4 cells do not, although the positive memory

cells co-stimulated the naive T cells with anti-CD3

antibodies to induce IL-2 production. The naive cells

were shown to express CD86 after co-stimulation

with CD86 and T-cell receptor ligation (92). A mouse

model showed that when T-cell donors from CD80/

CD86-deficient mice were used for allogeneic trans-

plant recipients, graft-vs.-host disease accelerated

compared with wild-type T cells. On the other hand,

T cells from CD86 transgenic mice that over-

expressed CD86, mediated the reduced graft-vs.-host

disease mortality. This study demonstrated the

importance of T-cell-associated B7 molecules as

negative regulators of immune responses (235). The

significance of down-regulation of CD86 on T cells in

periodontal disease is currently unknown.

Autoimmunity: natural killer Tcells

Mouse CD1d1 is a member of the CD1 family of

evolutionarily conserved major histocompatibility

complex antigen-like molecules (110). Unlike the

classical major histocompatibility complex products

that bind peptides, mouse and human CD1d mole-

cules present glycolipid antigens such as a-galacto-

sylceramide to CD1d-restricted natural killer T cells.

The use of CD1d knockout mice has demonstrated an

inability to clear metastatic tumors and a-galactosyl-

ceramide was able to inhibit disease in diabetes-prone

non-obese diabetic mice, suggesting a critical role for

CD1d-dependent T cells in various disease conditions

(102). Another study showed that CD1 expression

increased on antigen-presenting cells in Listeria-

infected mice and the use of anti-CD1 antibody

reduced transforming growth factor-b2 levels while

increasing IL-12 and interferon-c at disease onset. The

results pointed to a regulatory role for CD1-reactive

cells in the immune response to Listeria (224).

Mouse natural killer 1 cells constitute a subset of

T-cell receptor ab+ T cells that express natural killer

surface receptors. They are thought to play an

immunoregulatory role because of their ability to

secrete IL-4 within minutes of primary activation

(17), although another report demonstrated a rapid

production of both IL-4 and interferon-c in mice after

treatment with a-galactosylceramide (211). A unique

feature of their T-cell receptor repertoire is the

expression of an invariant T-cell receptor chain,

Va14-Ja281 in mice (18) and Va24-JaQ in humans

(177). A recent immunohistological study examined

natural killer T cells in periodontal disease and found

that the frequency of Va24-JaQ T-cell receptor-

expressing T cells was higher in periodontitis lesions

than in gingivitis tissues or peripheral blood. The

natural killer T cells also appeared to associate with

CD1d+ cells and it was suggested that these cells play

a regulatory role in periodontal disease (258).

Autoimmunity has been suggested to be a feature

of periodontal disease. Cross-reactivity of human

heat-shock protein 60 and P. gingivalis GroEL, which

is a bacterial homologue, has been shown in perio-

dontal disease (66, 225). Heat-shock protein

60-specific, as well as P. gingivalis cross-reactive, T

cells have also been demonstrated to accumulate in

periodontitis lesions (259). Taken together these data

suggest that both a humoral and a cell-mediated

specific immune response to heat-shock protein 60

may be important in the disease process. Addition-

ally, anti-collagen type l and lll antibodies have been

demonstrated in the gingivae of periodontitis pa-

tients (99) and collagen type 1-specific T-cell clones

have been identified in inflamed tissues of perio-

dontitis patients (248).

The study by Yamazaki et al. (258) suggests that an

immune response to autoantigens such as collagen

type I or heat-shock protein 60 may be well

controlled by natural killer T cells. A relationship

between a deficiency in natural killer T cells and

autoimmune diseases has been cited in mice (150,

231). An impairment of the subtle balance could be

involved in the pathogenesis of periodontal disease

(Fig. 2) The results however, did show increases of

natural killer T cells in periodontitis, suggesting a

functional role for these cells and because of their

ability to secrete rapid amounts of cytokines, they

may influence the T helper cytokine response. In

support of the above findings (258), CD1d is the most

prominent CD1 molecule in periodontitis and the

CD1d-expressing cells increased with increasing

number of invariant natural killer T-cell infiltration

(2). It is becoming clear that both bacterial and

27

The role of T cells in periodontal disease

endogenous glycolipids presented by CD1d can be

recognized by human natural killer T cells but in

some instances, the recognition of bacteria by natural

killer T cells may be indirect (146) (Fig. 3). One study

suggested that Salmonella infection may lead to an

altered environment, where natural killer T cells are

stimulated by inflammatory cytokines in combina-

tion with CD1d-mediated presentation of autologous

ligands, induced in response to infection (27). This

scenario could also be applicable to chronic inflam-

matory periodontal diseases in which inflammatory

cytokines are up-regulated.

However, down-regulation of CD1d in murine T

cells by P. gingivalis has been demonstrated (87)

implying that even though there may be higher

numbers of natural killer T cells in periodontitis,

these may not be functional if T-cell–natural killer

TLRsMicrobial

components(lipopolysaccharide,

lipoteichoic acid, etc.)

NKT cell

InA

direct mechanism

cytokines

CD1dEndogenous

glycolipid

Dendritic cell

Increased synthesis of these

moleculescytokines

B

microbial glycolipids

CD1 reactive T cell (NKT ells)

Direct mechanism

cytokines

CD1d

Dendritic cell

Microorganisms

CD1

glycolipid autoantigens

microbial glycolipids

Fig. 3. Indirect and direct mechanisms of CD1d-reactive

natural killer T-cell (NKT) activation. Microbial compo-

nents such as lipopolysaccharide, lipoteichoic acid and

other lipopeptides can be recognized by TLRs resulting in

increased synthesis of endogenous glycolipid. Natural

killer T cells recognize endogenous glycolipids presented

by CD1d. Natural killer T cells are also stimulated by

inflammatory cytokines induced in response to infection

(A). Microbial glycolipid can also be directly presented by

CD1d molecule, resulting in the activation of natural killer

T cells (B).

Fig. 2. Putative roles of autoimmune response and regu-

latory mechanisms in susceptible patients and non-sus-

ceptible patients. In susceptible patients (A), infection and

subsequent inflammation result in the up-regulation of

auto-antigens such as heat-shock protein 60 and collagen

type I and the activation of auto-reactive T and B cells

specific to those antigens. Although regulatory T cells are

induced in the lesion, their number and function may not

be sufficient to control immune pathology. In non-sus-

ceptible patients (B), on the other hand, the autoimmune

response stimulates scavenger cells to take up the

degenerated self-components resulting in acceleration of

the tissue repair process. These mechanisms may be well

controlled by regulatory T cells. Consequently, tissue

integrity is maintained and the stable lesion can be seen.

28

Gemmell et al.

T-cell interactions were a feature of periodontal dis-

ease. In addition to invariant natural killer T cells,

other phenotypes of regulatory T cells, possibly CD4+

CD25+ regulatory T cells, Th3 and Tr1 infiltrate and

may play roles in periodontal disease (159).

The role of autoimmunity in chronic inflammation

is still not clear. It is possible that autoimmunity is a

feature of all chronic inflammatory processes. In this

context it has been known for many years that gin-

gival fibroblasts are able to phagocytose collagen

such that anti-collagen antibodies may facilitate this

phagocytosis and hence the removal of broken down

collagen. At the same time an anti-heat-shock protein

response may enhance the removal of dead and

dying cells such that these autoimmune responses

may be a natural part of chronic inflammation.

Control of these responses would therefore be

essential, hence the increase in regulatory natural

killer T cells in periodontal tissues. This concept

further illustrates that the role of T cells in perio-

dontal disease may be one of immune homeostasis.

Further studies are clearly needed to test this hypo-

thesis and to determine the role of regulatory T cells

in periodontal inflammation.

Bone loss

Do T cells have a role in tissue destruction in peri-

odontal disease? It has been known for some time

that cells of the immune system can influence bone

cell function (132). Osteoclasts share a common

origin with cells of the macrophage/monocyte lin-

eage and respond to and produce cytokines that

regulate cells of this lineage. Osteoblasts originate

from bone marrow stromal stem cells of mesenchy-

mal origin and have the capacity to produce factors

that influence the lineage development of bone

marrow cells (132). Receptor activator of nuclear

factor-jB ligand (RANK-L), which is also known as

osteoprotegerin-L (OPG-L), regulates osteoclast dif-

ferentiation and function (229). The receptor for

RANK-L/OPG-L is RANK (4) and a variety of cells

produce a decoy receptor OPG, which when released

by cells, binds RANK-L/OPG-L to prevent activation

of RANK (210). While these factors have potent

effects on osteoclast development, they also have

regulatory effects on immune cell function (132).

Results of a study on RANK-L/OPG-L-deficient mice

showed that this factor is critical in T-cell maturation

and T cells in these mice showed poor induction of

cytokines such as interferon-c, IL-2, and IL-4 in re-

sponse to anti-CD3 and anti-CD28 (119). Increased

concentrations of RANK-L and decreased concen-

trations of OPG have been reported in the gingival

crevicular fluid from periodontitis patients compared

with control subjects and the ratio of RANK-L/OPG

was also significantly higher, suggesting that these

two factors contribute to alveolar bone destruction

in periodontal disease (152). A similar finding was

reported in another study with levels of RANK-L

being higher in active sites that were probably

associated with tissue destruction compared with

inactive sites (244). Interestingly, human gingival

fibroblasts were shown to express OPG rather

than RANK-L and OPG mRNA expression and pro-

duction by gingival fibroblasts was augmented

by lipopolysaccharide stimulation. Supernatants of

lipopolysaccharide-stimulated fibroblasts reduced

the numbers of tartrate resistant acid phosphatase-

positive cells generated by monocytes cultured in the

presence of RANK-L and macrophage colony-sti-

mulating factor, suggesting the inhibition of mono-

cyte-derived osteoclasts via an OPG pathway (156).

Gingival fibroblasts therefore may not play a role in

bone resorption in periodontal disease. Another

study by Liu et al. (130) supported the finding of

higher levels of RANK-L and lower levels of OPG in

advanced periodontitis. More significantly, RANK-L

mRNA was expressed mainly by inflammatory

lymphocytes and macrophages as well as prolifer-

ating epithelium in the vicinity of inflammatory cells.

Although both soluble and membrane-bound RANK-

L can be produced by activated T cells (119), the

frequency of RANK-L mRNA-positive gingival T-cell

clones was low but variable compared with the high

and constant frequency of other cytokines such as

interferon-c and transforming growth factor-b1

(105). This may reflect disease activity of the sites

from where the cells were extracted or the suscepti-

bility of the patients from whom the tissues were

obtained.

CD4 knockout mice, but not CD8 knockout mice,

lose less alveolar bone in response to oral P. gingi-

valis infection than immunocompetent mice of the

same genetic background, suggesting that CD4 cells

may contribute to bone resorption (14). Experiments

in non-obese diabetic/severe combined immunode-

ficient (NOD/SCID) mice transplanted with human

peripheral blood lymphocytes from periodontitis

patients and orally challenged with A. actinomyce-

temcomitans also showed that human CD4 cells but

not CD8 cells or B cells were able to mediate alveolar

bone destruction (237). This study also showed that

A. actinomycetemcomitans stimulated the production

of OPG-L by CD4 cells, while inhibition of OPG-L

29

The role of T cells in periodontal disease

function using OPG diminished bone destruction and

reduced the numbers of periodontal osteoblasts after

bacterial challenge. The authors acknowledged that

OPG-L produced by CD4 cells may not be the sole

inducer of increased alveolar bone destruction in

periodontal disease because injection of soluble OPG

for 4 weeks did not completely block this bone

destruction in vivo. An OPG-L-independent induc-

tion of osteoclast differentiation has been reported

(117). This study found that osteoclasts could be

generated from mouse bone marrow cells and this

was not inhibited by OPG.

As already stated, IL-1 has a major role in bone

resorption in periodontal disease and both IL-1 and

tumor necrosis factor-a have been reported to regu-

late the balance of OPG-L and OPG (100, 101) thereby

contributing to bone destruction independently of

cell-mediated immunity (237). In this respect, P. gin-

givalis was shown to down-regulate the gene expres-

sion for osteoclast stimulating factor 1 as well as for

IL-1b in CD4 cells (87), suggesting that P. gingivalis-

induced T cells may not play a role in the bone

resorptive process in periodontal disease. However,

even though B cells were shown not to contribute to

A. actinomycetemcomitans-induced bone resorption

in mice (237), as discussed earlier, P. gingivalis

induced IL-1b production by B cells rather than

monocytes (73). Therefore, with increased numbers of

B cells associated with disease progression, a link

between B cells and alveolar bone destruction in

human periodontitis may be more than possible.

Connective tissue matrixdestruction

Connective tissue remodeling occurs in growth and

development and is regulated by the interplay of

cell–cell and cell–matrix interactions involving the

production of enzymes, activators and inhibitors and

cytokines and growth factors (185). Proteinases such

as the metalloproteinases (MMPs) are key enzymes in

tissue degradation and this family of neutral pro-

teases is part of a larger class of metalloproteinases

that include the ADAMS (disintegrin and metallo-

proteinase domain) (187). MMPs produced by resi-

dent cells including fibroblasts, macrophages, and

epithelial cells and also inflammatory cells have been

cited as playing roles in tissue destruction in perio-

dontal disease (148, 195, 260) and are regulated by

tissue inhibitors of metalloproteinases (TIMP).

It has been suggested that tissue destruction in

disease processes may be the result of an imbalance

of metalloproteinases over tissue inhibitors (185).

The concentration of TIMP-1 in the saliva of patients

with periodontitis has been shown to be lower than

in the saliva of healthy subjects, while collagenase

activity was higher. Initial therapy resulted in recip-

rocal changes of TIMP-1 and collagenase levels.

Furthermore, collagenase in the healthy subjects

consisted mainly of procollagenase whereas in dis-

eased patients, active collagenase was found pre-

dominantly (94). Also, greater collagenase activity

was found in the gingival crevicular fluid of perio-

dontitis patients than in the fluid of control subjects

and the collagenase was demonstrated to be derived

mostly from neutrophils (245). MMP9 produced by

neutrophils was shown to be prominent not only in

the crevicular fluid but also in the gingival tissue

samples from patients with periodontitis (214, 250).

Latent MMP2 and MMP9 are expressed in the gingi-

val tissues of patients with periodontitis; active

MMP2 was only detected in tissues associated with

clinical disease (121) although another study sug-

gested a role for MMP9 in the gingival epthelial

response to periodontal infection (213, 214). Yet an-

other study suggested a role for both MMP2 and

MMP9 in tissue destruction in periodontitis (140)

while Seguier et al. reported increased amounts of the

active form of MMP9 in gingival tissue specimens of

periodontitis patients (195). Recently it has been

reported that P. gingivalis and A. actinomycetem-

comitans supernatants can activate MMP2 in human

periodontal ligament cells, although while A. actin-

omycetemcomitans induced a reduction in TIMP2

secretion, there was no change in the level of TIMP2

in the presence of P. gingivalis supernatants (239).

Although direct T-cell-derived metalloproteinases

have not been reported, our microarray study showed

that MMP9 and TIMP2 were down-regulated in CD4

cells (87).

The microarray study also demonstrated a down-

regulation of the gene for procollagen type III in CD4

cells. Whether or not the same is true for fibroblasts

remains to be determined. Both collagen type III and

fibronectin have been shown to be greatly dimin-

ished in inflamed gingiva (247), indicating a case for

P. gingivalis-induced type III collagen deficiency in

periodontitis. Transmission electron microscopy of

biopsies from patients with rapidly progressive peri-

odontitis and from adult periodontitis patients

demonstrated the almost complete destruction of

collagen types l and lll in areas with leukocyte infil-

tration while collagen types V and Vl were dominant

(97). Another study correlated the number of

inflammatory cells with the area of collagen fibers

30

Gemmell et al.

that was decreased in gingival connective tissues of

patients with severe periodontitis compared with

healthy controls. Second, increases in the amounts of

MMP1, MMP2, MMP3, and MMP9 and the active

form of metalloproteinase 9 were correlated with the

number of CD22+ B cells and CD68+ cells, which

would include macrophages and T-cell intracellular

antigen 1-positive cells (195), implicating T cells in

the production of metalloproteinases. However,

while P. gingivalis may down-regulate metalloprote-

inase 9 in T cells, metalloproteinase production by

other cells, including B cells, may be increased in

periodontitis.

Susceptibility to periodontaldisease

It is clear that variations in disease occur in indi-

viduals who harbor the same periodontal pathogens

in their dental plaque as well as in patients in whom

the bacterial composition varies (235). While perio-

dontopathic bacteria and the inflammation they

provoke are essential for disease progression, envi-

ronmental risk factors such as tobacco smoking,

psychosocial stress, and systemic diseases such as

diabetes modify the host response and may be

major determinants of the enormous variation in

susceptibility (172).

It also appears that genetic factors may determine

susceptibility or resistance to periodontal disease (12,

93). Results from family studies suggested that envi-

ronmental factors might be major determinants of

variation in periodontitis, although twin studies

indicated that both environmental and genetic

factors influenced disease progression (149). Inter-

estingly, although genetic predispositions to perio-

dontitis may involve defects other than those of the

immune response, including defects in collagen,

cementum, and epithelium (93), genetic control of

the immune response in periodontal disease is sig-

nificant because of the importance of immunity in

disease progression. In this respect, an animal model

study has shown that the CD4 cytokine response to

P. gingivalis depended on the H-2 haplotype (84),

indicating a strong genetic influence on T-cell

immunity to this periodontopathic bacterium.

To understand the extent to which the variation in

cytokine responses in periodontal disease may be

attributed to genetic determinants, genetic poly-

morphisms in cytokine genes have become an area of

research. Polymorphisms in the IL-1 cluster have

been a focus of attention since Kornman et al. (120)

demonstrated that genotype-positive individuals had

a 20-fold increased risk of developing severe perio-

dontitis after the age of 40 than those individuals who

are genotype negative (120). A recent microbiological

study of IL-1-positive and IL-1-negative adults

showed that significantly higher counts of bacteria,

including T. forsythia, P. gingivalis, T. denticola as

well as others, were detected in periodontal pockets

>6 mm in depth in genotype-positive subjects than

in individuals who were genotype negative (216),

suggesting that there may be a correlation between a

tendency of genotype-positive people to harbor these

bacteria in their plaque. In a 5-year longitudinal

study on the progression of periodontal disease,

Cullinan et al. (41) showed that while there was no

direct effect of the IL-1 genotype on disease pro-

gression there were interactive effects between the

IL-1 genotype, the presence of P. gingivalis and dis-

ease and between IL-1 genotype, smoking, and dis-

ease such that the IL-1 genotype could be considered

as a secondary risk factor for periodontal disease.

This study was the first to show the interactions be-

tween bacteria, genetics, and environment in the

progression of periodontal disease. In their review on

cytokine gene polymorphisms in periodontal disease

Taylor et al. (235) suggested that apart from IL-1

polymorphisms, a role for cytokine gene polymor-

phisms and susceptibility to chronic periodontitis

have not been established, although understanding

cytokine regulation and immune regulation in peri-

odontal disease remains of major concern.

Conclusion

Despite over 40 years of research into the immuno-

logy of periodontal disease the role of T cells remains

an enigma. It is clear from the data obtained from

the recent microarray study that in BALB/c mice,

P. gingivalis suppresses the T-cell response in a

number of ways including down-regulating the

expression of genes which affect the T-cell receptor–

CD3 complex, CD2 binding protein 2 and CD8

expression (87). The down-regulation of genes coding

for a number of cytokines and/or cytokine receptors

suggests a swing away from Th1 responses. Although

a concomitant up-regulation of genes encoding Th2

cytokines was not demonstrated, the overwhelming

results of this study demonstrated that down-regu-

lation of both CD4 and CD8 cells could also lead to

suppression of help for the antigen-specific B-cell

response in periodontitis if P. gingivalis was a major

dental plaque constituent. These results have led to

31

The role of T cells in periodontal disease

the development of the hypothesis that T cells have a

fundamental role in maintaining immune home-

ostasis in the presence of the plaque biofilm. In this

context it can be seen to be in the best interest of the

biofilm and of the host if a balance can be reached.

The T-cell response can therefore be considered to be

the default response where activation is balanced

with suppression. It is when this balance is disturbed

that disease progression occurs.

This hypothesis is based on findings using a mouse

model of P. gingivalis infection. However, mice do

not develop periodontal disease and the P. gingivalis-

induced immune response is a simple response to

one albeit significant periodontopathic bacterium. In

humans, dental plaque is a complex biofilm. Sub-

gingival plaque, which resides in a more protected

location than supragingival plaque, is not subject to

the same degree of intraoral abrasion or salivary host

defense mechanisms and as with biofilms in general,

is very resistant to removal (48). It is becoming clear

that clusters of bacteria occur (215) and each bac-

terium in the cluster is likely to affect the responses

induced by the others and vice versa. In this respect a

number of animal models have shown modulation of

the immune response by co-immunization with two

periodontal bacteria. Mice infected with P. gingivalis

together with F. nucleatum had significantly larger

skin lesions than those infected with P. gingivalis

alone while active immunization with P. gingivalis

protected against challenge with both organisms (58).

Chen et al. (36) reported that immunization of

A. actinomycetemcomitans together with P. gingivalis

resulted in first- and second-degree lesions com-

pared with first-degree lesions only, which followed

immunization with A. actinomycetemcomitans alone.

The serum anti-P. gingivalis response was higher in

mice injected with both organisms than in mice

injected with only P. gingivalis although this was not

observed with the anti-A. actinomycetemcomitans

antibody response. Another study showed that

although the levels of anti-F. nucleatum antibodies in

mice injected with F. nucleatum followed by P. gin-

givalis were the same as in mice immunized with

F. nucleatum alone, antibody levels to P. gingivalis

were very low. In contrast, mice injected with

P. gingivalis followed by F. nucleatum produced

equal levels of both anti-P. gingivalis and anti-F.

nucleatum antibodies, although at lower levels than

the other groups immunized with bacteria respect-

ively (83). Furthermore, the inhibition of neutrophil

phagocytosis of immune serum-opsonized P. gingi-

valis was shown to be modulated by the presence of

anti-F. nucleatum antibodies, while anti-P. gingivalis

antibodies induced an inhibitory effect on the phag-

ocytic response to F. nucleatum (85).These studies

highlight the complex often synergistic responses

with co-infection (55), which may have relevance to

the multibacterial infection found in human perio-

dontal disease.

The role of autoimmunity in chronic inflammation

is also of major interest. In this context it can be

postulated that autoimmunity is a critical and

integral part of chronic inflammation in that it

enhances the removal of collagen by enhancing

fibroblast phagocytosis of protease-digested collagen

fragments as well as the removal of destroyed or

dying cells. Control of this process by regulatory T

cells then becomes fundamental and again if there

is a disturbance in this homeostatic mechanism

enhanced tissue destruction could result.

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