Crucially, co-stimulatory molecules act together withthe antigen-specific signals before the T cell is sanctionedfor proliferation. Co-stimulatory and antigen-specificsignals must be present simultaneously on the same cell.

Overall, antigen presentation through MHC class I orclass II molecules can be split into four stages adhesion,antigen-specific activation, co-stimulation, and cytokinesignaling (see Fig. 7.1).

Multiple cell surface molecules interactduring antigen presentation to T cellsIntercellular adhesion molecules (ICAMs), particularlyICAM-1 (CD54), interact with the integrin, lymphocytefunctional antigen-1 (LFA-1 or CD11a/CD18), presenton all immune cells.

If mouse cells are transfected with both human MHCand human ICAM-1, their capacity to act as human APCsis augmented.

When the T cell encounters the appropriate MHCmoleculepeptide, which happens rarely except during an ongoing infection, a conformational change in LFA-1on the T cell, signaled via the TCR, results in tighterbinding to ICAM-1, which results in prolonged cellcellcontact. The joined cells can exist as a pair for longperiods, allowing time for the T cell to proliferate anddifferentiate.

The specific MHC moleculepeptideTCR interac-tion, though necessary, is not sufficient to fully activate theT cell. A second signal is required, otherwise the T cellwill become unresponsive. This second signal, alsoreferred to as co-stimulation, is of crucial importance.

Some co-stimulatory molecules that interact withligands on the T cells surface are shown in Fig. 7.16.

The most potent co-stimulatory molecules known areB7s, which are members of the immunoglobulin super-family molecules; they include B7-1 (CD80) and B7-2(CD86).

Several other B7-related molecules are beginning toemerge.

B7s exist as homodimers on the cell surface. Theseproteins are constitutively expressed on DCs, but can beupregulated on monocytes, B cells, and probably otherAPCs.

Upregulation of co-receptors is stimulated by inflam-mation and by interaction of microbial products with Toll-like receptors (TLRs, see Fig. 6.24) on the APC.

Co-receptors are the ligands for other immunoglobulinsuperfamily molecules CD28 and its homolog CTLA-4(CD152), which is expressed after T cell activation. CD28is the main co-stimulatory ligand expressed on naive Tcells. CD28 stimulation: has been shown to prolong and augment the pro-

duction of IL-2 and other cytokines; and is probably important in preventing the induction of

tolerance. Although the CD28B7 interaction is extremely impor-tant, CD28 knockout mice do respond to antigen, butrequire higher doses, so CD28 triggering is not oblig-atory, even for naive T cells. In CD28 knockout miceother co-stimulatory signals probably replace that deliv-ered by CD28B7.

CTLA-4, the alternative ligand for B7, is an inhibitoryreceptor limiting T cell activation, resulting in less IL-2production. Thus CD28, constitutively expressed, initiallyinteracts with B7, leading to T cell activation. Once thishas peaked, the upregulation of CTLA-4 with its higheraffinity limits the degree of activation because available B7will interact with CTLA-4 (Fig. 7.17).

Q. What effect would you expect to see in mice that havethe CTLA-4 gene knocked out?A. They suffer from an aggressive lymphoproliferative disorder,because they do not inactivate dividing T cells efficiently (seeFig. 7.17).

CO-STIMULATORY MOLECULES ARE ESSENTIAL FOR T CELL ACTIVATION

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Critical molecules involved in antigen presentation

Fig. 7.16 The molecules involved in the interaction between Tcells and APCs. The various cytokines and their direction ofaction are also shown. In humans LFA-3 (CD58) acts as aligand for CD2, but in rodents CD48 performs this function.

T cell

IL-1IL-6TNF!IL-12IL-15

IFN"GM-CSF

IL-4TNF#

LFA-1 TCR CD28CD2

CD4

p56Lck

APC

ICAM-1 class IILFA-3(CD48)

B7-1/B7-2(CD80/CD86)

Role of CTLA-4 in controlling T cell activation

Fig. 7.17 Before activation, T cells express CD28, whichligates B7-1 and B7-2 on APCs (e.g. B cells). After activation,CTLA-4 is expressed, which is an alternative high-affinityligand for B7. CTLA-4 ligates B7, so the T cells no longerreceive an activation signal.

T

T

T

APC APC

inactivation

activationdivision

CD28B7

CTLA-4

B7