Effector Mechanisms ofEffector Mechanisms ofCellCell--Mediated ImmunityMediated Immunityyy

Cell Mediated ImmunityCell Mediated Immunity

• Historically, immunologist have dividedadaptive immunity into namely:

• CMI, which can be adoptively transferredonly by viable T lymphocytes andonly by viable T lymphocytes and

• humoral immunity, which can beadoptively transferred with serumcontaining antibodies.

Cell Mediated ImmunityCell Mediated Immunity

• General responses by CMI, include:•Facilitate innate immune response to

bacteriaA ti i l•Anti-viral

•Anti-fungal•Anti-tumor•Transplantation rejection

Cell Mediated ImmunityCell Mediated Immunity• Many microbes have developed

mechanisms that enable them to surviveand even replicate within phagocytes, sothe innate immunity is unable to eradicateinfections by such microbes.

• In CMI against phagocytosed microbes,the specificity of the response is due to Tcells – but the actual effector function ismediated by the phagocytes.

• CD4+ TH1 cells andCD8+ T cells recognizeclass II MHC-associated or class IMHC-associatedpeptide antigens ofphagocytosedp g ymicrobes, respectively,and produce cytokines(IFN-γ, TNF) thatactivate the phagocytesto kill the microbes andstimulate inflammation.

Listeria monocytogenesListeria monocytogenes• Protection to Listeria

infection can beadoptively transferredby infusing T cellsfrom an infectedmouse into a naïvemouse.

• This experiment wasperformed in 1950 byGeorge Mackaness.

DelayedDelayed--type Hypersensitivitytype Hypersensitivity

• There is a hypersensitivity condition thatalso demonstrates the T cell activation ofmacrophages.

• Delayed type hypersensitivity (DTH) is• Delayed-type hypersensitivity (DTH) isresponsible for tissue injury due to Mφ andpro-inflammatory cytokine release.

• DTH will be discussed in thehypersensitivity lectures.

DTH

Fig. 13-12

DTH

Fig. 13-13

Cell Mediated ImmunityCell Mediated Immunity

• In a classicalsense of CMI,CD8+ lymphocyteskill non-phagocytickill non phagocyticcells infected withmicrobes.

Cell Mediated ImmunityCell Mediated Immunity

• CMI in response to helminthic parasitesis mediated by TH2 cells that stimulatethe production of IgE and activation ofeosinophils.

Cell Mediated ImmunityCell Mediated Immunity• Cell-mediated immune responses consist

of the development of effector T cells fromnaïve cell in peripheral lymphoid organs,migration of these effector T cells andth l k t t it f i f tiother leukocytes to sites of infection,

through:• either cytokine-mediated activation of

leukocytes to destroy microbes or• direct killing of infected cells.

Cell Mediated ImmunityCell Mediated Immunity

• Keep in mind that naïve T cells do notproduce effector cytokines or themolecules to kill other cells.

• The development of the effector T cells of• The development of the effector T cells ofCMI involves the sequence of antigenrecognition, clonal expansion, anddifferentiation – as we have previouslydefined.

Cell Mediated ImmunityCell Mediated Immunity

• CD4+ cells may differentiate into subsetsof effector cells that produce distinct setsof cytokines and therefore distinct effectorfunctionsfunctions.

• These effector cell have been previouslydefined by us as TH1 and TH2.

THTH11 and THand TH22• The control of TH polarization is through

the dendritic cell.• DC1 polarizes TH1 through IL-12• DC2 polarizes TH2 through IL-4DC2 polarizes TH2 through IL 4• DC1 function appears to be through Toll-

like receptors that bind bacterial DNAmotifs (reviewed p 282-283).

• DC2 function appears to be thoughincreased levels of cAMP.

TollToll--like receptorslike receptors• Toll-like receptors (TLRs) are a family of pattern

recognition receptors that are activated byspecific components of microbes and certainhost molecules.

• INNATE RESPONOSE: They constitute the firstyline of defense against many pathogens andplay a crucial role in the function of the innateimmune system.

• ADAPTIVE RESPONSE: TLRs were observedto influence the development of adaptiveimmune responses, through activating antigen-presenting cells, DC1.

TollToll--like receptors (TLR)like receptors (TLR)• TLRs are type I transmembrane proteins• TLR3 recognizes dsRNA, a viral product• TLR9 recognizes unmethylated CpG motifs

frequently found in the genome of bacteria andi b t t t b tviruses, but not vertebrates.

• TLR7 recognizes small synthetic immunemodifiers including imiquimod, R-848, loxoribine,and bropirimine, all of which are already appliedor promising for clinical use against viralinfections and cancers.

TollToll--like receptors (TLR)like receptors (TLR)

• Plasmacytoid dendritic cells express TLR7and TLR9, and respond to TLR7 andTLR9 ligands by producing a large amountof IFN-αof IFN α.

• TLR3, TLR7 and TLR9 play an importantrole in detecting and combating viralinfections.

THTH11vsvs

THTH22THTH22

THTH11• TH1• The polarization to TH1 can be stimulated by

intracellular bacteria and viruses that infectmacrophages.

• A second pathway already described is microbeA second pathway already described is microbeengagement of TLR.

• A common feature of these infections is that theyelicit innate immune reactions with theproduction of IL-12.

• Enhancement of IL-12 production is through THCD40L with APC CD40.

THTH11TH1• IL-12 binds to CD4+ cells and activates

STAT4, a transcriptional factor thatpromotes TH1 polarization.

• IFN-γ also induces T-bet, a transcriptionalfactor that enhances the TH1 polarization.

• IFN-γ stimulates further production of IL-12by APCs and IL-12r on the lymphocyte.

TH1TH1

THTH11 and THand TH22TH2• The differentiation of antigen stimulated T

cells to TH2 is dependent on IL-4.• IL-4 activates the transcriptional factorp

STAT6.• GATA-3 transcriptional factor, increases

due to antigen presentation and enhancesthe transcription of TH2 cytokine genetranscription.

Fig. 13-7

CTLCTL--KillingKilling

Effector Mechanisms: TEffector Mechanisms: T--cellscells

• Chapter 6

• Accessory Molecules of T-cells.

• Adhesion molecules.

IntegrinIntegrin• A concept has evolved suggesting that T

cells initiate antigen-independent adhesiveinteractions with apposing cells to scan thesurface for specific antigen, followed bysurface for specific antigen, followed byeven stronger antigen-dependentadhesive interactions that would allow forspecific activation of T-cell proliferation,cytokine production, or the delivery of alethal hit to the target cell.

IntegrinsIntegrins• Integrins are important for many different

physiologic processes, includingembryogenesis, thrombosis, wound healing,tumorigenesis and immune responses.

• The integrin supergene family consists of ag g ynumber of cell surface αβ heterodimers.

• The α and β chains are type I transmembraneglycoproteins with a single hydrophobictransmembrane domain, a short cytoplasmic tail,and an extracellular domain that associatesnoncovalently to form the heterodimer.

tegr

ins

Inte

grins

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IntegrinsIntegrins

• In the immune system, the most importantintegrins, those of the β1, β2, and β7subfamilies, participate in T-cell migrationand provide stimulatory signals for T-celland provide stimulatory signals for T cellproliferation and effector functions.

IntegrinsIntegrins• T-cell migration into tissues requires T-cell

binding to and extravasation throughendothelium, an integrin-dependentprocess.

• Current models propose that chemokinesdeliver the critical biochemical signals thatpromote endothelial binding through theupregulation of integrin avidity on the Tcell.

IntegrinsIntegrins• Integrin-mediated events are also critical for T

cells that participate in immune surveillance.• As resting T cells circulate through the blood,

they adhere specifically to the specializedy yendothelium of the postcapillary venules ofsecondary lymphoid organs or HEVs andextravasate from the bloodstream into theunderlying secondary lymphoid tissues.

IntegrinsIntegrins• How do the adhesion molecules regulate

their binding activity to allow both theattachment as well as detachmentcharacteristics required for transmigrationinto and out of the inflamed endotheliuminto and out of the inflamed endotheliumand draining lymph nodes?

• Lymphocytes have solved this problem bytightly regulating the affinity and avidity ofintegrin receptors.

IntegrinsIntegrins

IntegrinsIntegrins• These conformational changes are

dependent on the presence of specificdivalent cations, which are bound by theextracellular domains of integrins.

• Replacement of bound Ca2+ with Mg2+ forβ2 integrins or Mn2+ for β1 integrins resultsin increased receptor affinity for theirligands

IntegrinsIntegrins