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Memory T cells respond much faster to the Ag thannave T cells. Thus, in the case of infection, they helpto eliminate pathogens at an early stage, therebyeffectively preventing the disease spreading.

Composition of the T cell networkLymphoid organs

The primary LYMPHOIDORGANS the BONEMARROWandthymus are sites of HEMATOPOIESISand clonal selec-

tion of T cells. The T cell-mediated immune responsebegins in the secondary LYMPHOID ORGANS: spleen,lymph nodes, and organized lymphoid tissues associ-ated with mucosal surfaces including PEYERSPATCHES,tonsils, bronchial, nasal, and gut-associated lymphoidtissues. The secondary LYMPHOID ORGANS have spe-

cialized T cell-rich zones where nave T LYMPHOCYTESare concentrated; these include the periarteriolarlymphoid sheath of the spleen (PALS) and the para-cortex of the lymph nodes. Nave T cells reside in thespleen for just a few hours and in the lymph nodesfor about 1 day before they leave viasplenic veins or

16 T cell subsets and T cell-mediated immunity

CD4CD8

Lym

phoid

Tissu

e

Peripheral

Tissue

activation

proliferation

activation

Th TEM TEMCTL

effector effectoreffector memory effector memory

TCM

TCM

CCR7

CD45RO

CCR7

CD45RO

CCR7

CD62L

CCR7CD62L

FIGURE1. DEVELOPMENTOFT CELL-MEDIATEDRESPONSESISASEQUENTIALPROCESSAntigen-presenting cells (APC) can take up antigen (Ag) in peripheral tissues and migrate to secondary lymphoid tis-

sues. Nave T cells will be activated by recognition of MHC-peptide complexes on the APC, proliferate and differenti-

ate into effector or memory T cells. Both CD8 (CTL) and CD4 (Th) effector T cells will migrate to peripheral tissues to

exert their function. In addition, memory T cells can develop into CCR7- effector memory cells (TEM) that will migrate

to peripheral tissues or CCD7+central memory T cells (TCM). These, in turn, can recirculate through lymphoid tissues.

CCR7 is a chemokine receptor involved in T cell homing into lymphoid tissues.

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viaefferent lymphatic vessels, respectively. Migratingnave T cells eventually reach the bloodstream andsoon after enter new LYMPHOIDORGANS, repeating thecycle until they become activated by antigenic pep-tides or die by neglect.

T cell subsets

Thymic selection results in the appearance of T cellswith two types of TCR. The majority express Ag-bind-ing chains in the TCR, which are disulfide-linkedheterodimers of Ig superfamily proteins (Fig. 2),forming unique structures on each T cell. TCR Tcells have a very diverse REPERTOIREof Ag recognitionRECEPTORS and represent mature T cells that circu-late through the secondary LYMPHOID ORGANS anddevelop adaptive immune responses. A small frac-

tion of the T cells express chains in TCR, appear tobe much less heterogenic than TCR T cells, residein skin and certain mucosal surfaces, and may playa role in the initial response to microbial invasion.Although the functions of TCR T cells are not fullyunderstood, they are considered to be a relativelyprimitive part of the innate T cell response and willnot be reviewed in this chapter.

TCR T cells are subdivided into several groupson the basis of lineage markers and functional activi-ties. Two major surface co-RECEPTORmolecules, CD4and CD8, define two separate T cell lineages withdifferent functions. CD4+ cells recognize Ag in thecontext of MHC class II molecules (only expressedon so-called professional APC such as B cells, MAC-ROPHAGESand DC) and produce CYTOKINESas effectorT helper cells. CD8+ LYMPHOCYTES are activated byantigenic peptides presented by MHC class I mol-ecules (expressed on all nucleated cells) and formeffector CYTOTOXICT LYMPHOCYTES(CTL).

On the other hand, the functional status of the Tcells allows us to distinguish nave, effector, and mem-ory cells, as each of these displays extensive diversity

in terms of phenotype, function, and anatomic dis-tribution. Nave T cells are the most homogenousrepresentatives of CD4+and CD8+subsets. Upon acti-vation, however, they can be further distinguished bytheir cytokine profiles. Thus, activated CD4+T helpercells can be subdivided into Th1, Th2, Th17 and Treg

subsets based on production of signature CYTOKINES.In the case of the Th1/Th2 dichotomy, the character-istic CYTOKINESare: IFN-(Th1) versusIL-4, IL-5 (Th2)[1]. CD8+LYMPHOCYTESalso can be assigned to Tc1 orTc2 subsets according to their cytokine profile [2],although they do not produce the same quantitiesof CYTOKINES as CD4+ helpers and are not efficientin B cell activation (see chapter A3). Theoretically,both effector and memory LYMPHOCYTESof CD4+andCD8+ lineage can be divided into subsets based onthe above criteria. In addition, there are subsets of

regulatory T (Treg) cells that make T cell heterogene-ity even more complex. Treg cells can be subdividedinto naturally arising cells (nTreg) that are generatedin the thymus, and inducible Treg (iTreg) that areconverted into Treg upon activation in the periphery[3]. Many of the specific cell surface markers repre-

17Composition of the T cell network

FIGURE2T cell receptor complex consists of heterodimers

responsible for antigen recognition and CD3 molecules

involved in intracellular signaling. Immunoglobulin-like

chains are formed upon gene rearrangement and have

high variability among individual T cells. Non-polymor-

phic CD3 chains (, , , ) contain intracellular immuno-

receptor tyrosine-based activation motifs (ITAMs) initiat-

ing cascades of signal transduction.

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senting various T cell subsets can be very useful inthe design of drugs for selective manipulation of theimmune response.

T cell subset markers

Nave T cell markers

Nave T cells circulating in the blood, express L-selec-tin (CD62L), CC chemokine RECEPTOR7 (CCR7) andleukocyte function antigen-1 (the L2 integrinLFA-1). These mediate the ROLLING, adhesion, andextravasation of the cells through the high endothe-

lial venules (specialized venules found in lymphoidtissues) in peripheral lymph nodes and mucosalLYMPHOIDORGANS.

Survival of nave cells is maintained by low-AFFINITYTCR/self-Ag interaction and signaling as wellas by the presence of IL-7. These signals are normally

sufficient to maintain homeostasis of nave T cells forseveral months.

Effector T cell markers

High-AFFINITY interactions of TCR with foreign anti-genic peptide/MHC on mature APC following activa-tion are reflected in phenotype changes. Activated Tcells express CD69 (a very early activation antigen)and CD25 (IL-2Ra). Other important surface RECEP-TORS of activated T cells are: CD40 LIGAND, whichstimulates APC through binding to CD40, leading tothe up-regulation of CD80 (B7-1) and CD86 (B7-2)on APC; CD28, which binds to CD80 and CD86 andpropagates a costimulatory signal, thereby enhanc-ing growth factor (IL-2) production and increasingT cell activation.

Tumor necrosis factor (TNF) RECEPTOR familymolecules OX-40, CD27, and 4-1BB, also can befound on primary activated T cells. These RECEPTORSwere found to sustain T cell proliferation and sur-vival of activated T LYMPHOCYTESupon their bindingto the corresponding ligands on the APC. At thepeak of their proliferation, CD4+EFFECTORCELLSwerealso found to change the pattern of adhesion RECEP-TORSsuch as CD62L and sPSGL-1 (sialyated form ofp-selectin glycoprotein LIGAND 1) and chemokineRECEPTOR CXCR5. CD8+ CTL could also be charac-terized by expression of perforin and granzymes,proteins required for cytolytic functions. A particu-lar set of surface markers may predict the homingcapacity of effector T cells. For example, CXCR5RECEPTOR helps CD4+ CD62L, sPSGL-1, CXCR5+T cells to migrate into B cell-rich FOLLICLES of thelymph nodes and support ANTIBODY production.In contrast, absence of CCR7 and CD62L on CTLallows them to migrate into inflamed non-lymphoidtissues such as lung or gut and to clear pathogenicagents in these tissues.

Memory T cell markers

Memory T cells, unlike effector T cells, are notblasts nor do they enter the cell cycle. However,they are capable of circulating in lymphoid and

18 T cell subsets and T cell-mediated immunity

TABLE1. PHENOTYPICMARKERSASSOCIATEDWITHNAVE,EFFECTORORMEMORYT CELLSMany proteins are up-regulated or down-regulated rap-

idly after T cell activation, e.g., adhesion molecules or

molecules involved in effector functions.

nave effector TEM TCM

CCR7 +++ +/ +++

CD62L +++ +/ +++

CD45RO + +++ +++ +

CD45RA +++ + ++

CD95 +/ +++ ++ +/

Granzyme B +++ +/

CD25 +

CD127 ++ +/ + +++

CD28 ++ + ++

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non-lymphoid compartments. According to the loca-tion, memory T cells are divided into central andeffector memory cells and express correspondingsurface markers. For example, among three pheno-types of CD8+memory cells that have been identi-fied (CD45RA, CCR7+; CD45RA, CCR7; CD45RA+,

CCR7), the CCR7+T cells are non-CYTOTOXICcentralmemory cells, while CCR7 are effector memorycells [4]. Upon contact with the appropriate Ag,effector memory cells can execute effector functionsinstantly, whereas central or lymphoid memory cellscan rapidly proliferate, expanding and acquiringeffector functions. CD4+memory cells also appearto be heterogenic. At least two subsets of CD45RACD4+memory cells have been identified in humans.The central memory cells express CCR7 and CD62Land reside in LYMPHOIDORGANS, producing IL-2uponstimulation. Some of these have been found to

migrate into certain INFLAMMATION sites dependingon the expression of chemokine RECEPTORS such asCCR4, CCR6, and CXCR3. The other CCR7 subsetwith low CD62L expression produces IFN-and IL-4upon stimulation and apparently represents effectormemory cells.

Effectors of T cell-mediated immunity

CD4+helpers

Two major functional T helper subpopulations aredistinguished by their cytokine profiles (Fig. 3). Th1cells produce mainly IFN-, but also IL-2, TNF-, andlymphotoxin. Th1 cells enhance pro-inflammatoryCELL-MEDIATED IMMUNITY and were shown to inducedelayed-type HYPERSENSITIVITY (DTH), B cell produc-tion of opsonizing ISOTYPESof IgG, and mediate theresponse to some protozoa like Leishmania andTrypanosoma. Th2 cells secrete IL-4, -5, -6, -10 and -13and promote non-inflammatory immediate immuneresponses; they have been shown to be essential in

B cell production of IgG, IgA, and IgE. Th1 and Th2development routes appear to be mutually antago-nistic. This has given rise to the model of polarizationof immune response in accordance with the natureof the Ag and the surrounding cytokine milieu. Forexample, IFN-and IL-12 are known to support Th1

cells, while IL-4 and IL-10 assist Th2 development.Although the evidence for the polarized cytokinesecretion profiles of Th1 and Th2 is indisputable,several recent studies have shown more complexpatterns of cytokine interaction in different modelsof immune response, including autoimmune models

that are inconsistent with the simple dichotomyparadigm.

Since CD4+T cells are central in the origin andregulation of AUTOIMMUNITY, emphasis has beenplaced on the characterization of Th subsets andtheir possible roles in the inflammatory process. Withthe discovery that the p40 subunit of the pro-inflam-matory cytokine IL-12 can not only dimerize withthe p35 subunit to form IL-12, but also with p19 tocreate IL-23, the former dogma that IL-12-driven Th1responses were the critical contributors to INFLAM-MATIONhad to be revised [5]. It was found that IL-23

induced production of CD4+T cells that secrete pro-inflammatory cytokine IL-17A. Subsequently, thesecells were characterized as a separate Th subset,called Th17. Th17 cells are regarded as a majoreffector lineage with pro-inflammatory actions in dis-eases like RHEUMATOIDARTHRITIS, psoriasis and Crohnsdisease. Contribution of Th1 cells to inflammatorydiseases is still possible, although complex, given theadditional regulatory contributions of IL-12 and IFN-in INFLAMMATION.

Th17 cells also play a prominent role in infec-tion. In fact, Th17 is the first subset that is generatedduring infection. The IL-17 RECEPTORis expressed onfibroblasts, epithelial cells and keratinocytes. Contactwith IL-17 leads to production by the latter cell typesof IL-6 and CHEMOKINES like CXCL8 and CXCL2 andgranulocyte macrophage colony stimulating factors(GM-GSF). Altogether, this leads to recruitment ofNEUTROPHILSand MACROPHAGES into the site of infec-tion and enhances the BONEMARROWproduction ofthese cells. IL-22 produced by Th17 cells co-operateswith IL-17 in the induction of ANTIMICROBIAL PEPTI-DES, such as -DEFENSINS in epidermal keratinocytes,

thereby enhancing the innate acute inflammatoryresponse in infection.It is anticipated that a growing spectrum of Th

subset lineages will be discovered, defined by theexternal stimuli they respond to and the transcrip-tion factors they can induce (see Fig. 3). IL-12, IFN-

19Effectors of T cell-mediated immunity

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and transcription factors STAT1, STAT4 and T-bet leadto the production of Th1 cells. IL-4 in combinationwith STAT6 and GATA-3 generates Th2 cells. FollicularT helper cells (TFH) were recently defined to developunder the influence of IL-6 and transcription factorBcl-6. Th17 cells develop in the presence of TGF-,IL-6 and IL-23 and are characterized by the transcrip-tion factors RORt, ROR and STAT3. Recently, Th9cells also were proposed, a subset that develops

under the influence of IL-4 and TGF-and that pro-duces IL-9 [6].There are now several subsets which may

have potential to produce immunological disease.Adoptive transfer of Th1 or Th17 cells produces EAEand uveitis. Colitis in mice is produced by Th1, Th2,

Th17 and Th9 cells. TFHcan mediate the pathogenicANTIBODY response in experimental lupus models[7].

CD8+cytotoxic T lymphocytes

CTL are derived from activated nave CD8+cells, pro-liferate in the presence of IL-2, and can expand their

number many thousand-fold at the peak of a primaryimmune response. The dramatic clonal expansionof CD8+CTL in comparison to CD4+cells can mostlikely be attributed to the relatively easy activationby the Ag-MHC class I complex and better survivalin the circulation. Rapid expansion and the ability

20 T cell subsets and T cell-mediated immunity

FIGURE3. DIFFERENTIATIONOFEFFECTORT CELLSAg-activated T cells will differentiate into different phenotypes depending on the cytokines in the local environment

and can be characterized by their cytokine profile and by transcription factors. Th1 cells produce IFN-and IL-2 and

express T-bet. Th2 cells produce IL-4, IL-5 and IL-13 and express GATA3. Th17 cells produce IL-17 and IL-22 and

express ROR- t. Treg can be divided into different subsets based on the expression of FoxP3 and/or the production

of IL-10, TGF-and IL-35.

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of single CD8+CTL to destroy more than one TARGETcell, while sparing innocent bystanders, make CTLvery efficient Ag-specific EFFECTORCELLS. Destructionof selected cells by CTL requires the establishment ofcell contact with the TARGETcell and Ag recognition,thus initiating the release of cytolytic granules into

the immunological synapse. CTL, unlike nave T cells,do not require COSTIMULATORY SIGNALSupon Ag rec-ognition in order to kill. Therefore, they can destroy avariety of TARGETcells bearing foreign Ag.

Mechanisms of cell-mediated cytotoxicity

Two major pathways of CYTOTOXICITY have beendescribed in CTL: Ca2+-dependent perforin/gran-zyme-mediated APOPTOSIS, and Ca2+-independent FasLIGAND/Fas-mediated APOPTOSIS (Fig. 4). Both path-

ways are initiated via TCR signaling. Lytic granules[secretory lysosomes containing granzymes, per-forin (PFN) and the proteoglycan serglycin (SG)][8] appear to be transported into TARGET cells as

one complex. Granzymes are effector moleculescapable of inducing APOPTOSIS in TARGET cells viacaspase-dependent and -independent mechanisms.Granzymes enter into the TARGET cell directly viaplasma membrane pores formed by PFN or viaRECEPTOR-mediated endocytosis. In the latter case,

PFN mediates the translocation of granzymes fromendocytic vesicles into the cytosol. ProteoglycanSG presumably serves as a chaperone of PFN untilthe complex reaches the plasma membrane of theTARGETcells. Lytic granules represent a very efficientNATURALdrug delivery system.

Fas-mediated APOPTOSIS is initiated by binding ofFas molecules to the TARGETcell viaFas LIGANDon theCTL. The Fas molecule is a member of the TNF RECEP-TORsuperfamily with an intracellular death domaininitiating caspase-dependent APOPTOSIS upon bind-ing to Fas LIGAND. TCR cross-linking was shown to

induce up-regulation of Fas LIGAND expression onthe cell surface of CTL and in cytolytic granules.Fas-mediated APOPTOSISappears to be a general phe-nomenon not restricted to CTL. It was found to be

21Effectors of T cell-mediated immunity

FIGURE4. CTL CYTOTOXITYCANBEMEDIATEDBYTWODISTINCTPATHWAYSOne mechanism is via secretion of perforin and granzyme B from cytolytic granules. Perforin creates pores in the mem-brane of the target cell to enable granzyme B entry into the cell. Granzyme activates caspases that induce apoptosis.

The second mechanism is via interaction between CD95 (Fas) and CD95L (FasL). TCR-mediated activation induces

CD95L expression on the CTL. Binding of CD95 on the target cells will induce sequential caspase activation, leading

to apoptosis.

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involved in control of cell proliferation and homeo-stasis among other cells.

Regulatory T cells

Regulatory T cells (Treg), include more than onecell type critical in the maintenance of peripheralTOLERANCE, down-modulation of the amplitude of animmune response, and prevention of AUTOIMMUNEDISEASES. There is enough evidence at present toconclude that Treg participate in all cell-mediatedimmune responses, directly affecting Th1, Th2, Th17,CTL, and B cell reactions against self and foreignAg. The mechanisms by which Treg exert their func-tion are still not completely clear, but immunosup-pressive CYTOKINESsuch as TGF-, IL-10and IL-35 playan important role.

Although the majority of Treg appears within theCD4+T cell set, suppressor activity was also reportedamong CD8+T cells. Over the last few years, however,most attention was focused on CD4+regulatory cellsand particularly the nTreg, which are characterizedby constitutive expression of the -chain of the IL-2RECEPTOR (CD25) and the transcription factor Foxp3[9]. nTreg arise from the thymus and represent about10% of the total CD4 population.

Foxp3 is essential in the development and func-tion of nTreg. The absence of functional Foxp3 resultsin severe systemic AUTOIMMUNEDISEASESin mice andman. Foxp3 inhibits IL-2 transcription and inducesup-regulation of Treg-associated molecules, such asCD25, CTLA-4 and GITR [10], that can down-regulatethe immune response of adjacent cells.

In addition to nTreg, iTreg develop in the periph-ery from nave CD4+ T cells in the presence ofTGF-and IL-10, or in the absence of COSTIMULATION,especially in mucosal tissues. Within the populationof iTreg the heterogeneity is even more complex.Tr1 cells [11] depend on IL-10 for their inductionand their suppressive action, whereas Th3 cells [12]

depend on TGF-for their suppressive action.The inhibitory effect of all Treg primarily requiresstimulation of the TCR. Upon activation, cells maymediate their function viadirect cell contact throughinhibitory molecules such as CTLA4, but they mayalso function viasecretion of IL-10and TGF-. IL-10

can suppress differentiation of Th1 and Th2 cellsdirectly by reducing IL-2, TNF-and IL-5 production,and also indirectly by down-regulating MHC andCOSTIMULATORYMOLECULESon APC, thereby reducingT cell activation. The mechanism of suppression willmost likely depend on the type of Treg, the nature of

the immune response, the Ag and the site of INFLAM-MATION(Fig. 5) [13].

Mechanisms of T cell activation

Antigen presentation

Antigenic peptides are derived by different molecu-lar mechanisms of Ag processing, from pathogensresiding either in the cytosol or in vesicular compart-

ments of the infected cell. MHC class I moleculesbind to the antigenic peptides, which originate in thecytosol of APC as a result of a multimolecular com-plex of proteases (proteasomes) and are transportedto the endoplasmic reticulum by TAP-1 and TAP-2(transporter associated with Ag processing-1 and-2). The newly assembled MHC/peptide complexesin the endoplasmic reticulum are then translocatedthrough the Golgi to the cell surface. Virtually all cellsof the body express MHC class I molecules at differ-ent levels, and thus present antigenic peptides toCD8+CTL and become potential targets of destruc-tion, depending on the Ag.

MHC class II molecules, in contrast, bind peptidesderiving from pathogens that appear in intracellularvesicles of the cell or from extracellular proteinsinternalized by endocytosis. MHC class II moleculesare transported from the Golgi to endosomes and lys-osomes as a complex bound to the non-polymorphicinvariant chain instead of a peptide. Subsequently,the invariant chain is degraded and replaced withpeptides generated by vesicular acid proteases atacid pH in the endosomal compartments. MHC class

II/peptide complexes appear on the surface of onlya few types of immune cells, including MACROPHAGES,B cells, and DC [14].

Another important mechanism is cross-presen-tation of Ag, a process in which professional APCmay present an Ag transferred from other cells. This

22 T cell subsets and T cell-mediated immunity

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enables extracellular Ag to be presented by MHCclass I and to activate CTL. Several studies have shownthat DC can actually initiate a T cell response againstMHC class I-restricted Ag by cross-presentation. Cross-presentation also may serve as a mechanism for Tcell TOLERANCEto self-Ag in the periphery [15].

Molecular mechanisms of T lymphocyteactivation

Activation of nave T cells is the most critical step

in developing immunity and requires a complexinteraction of TCR, co-RECEPTORS, and accessory mole-cules on the surface of the T cell with correspondingligands on the APC (Fig. 6). TCR-Ag/MHC interactionprovides an Ag recognition step and initiates intrac-ellular signaling. Co-RECEPTORSsuch as CD4 and CD8

assist the TCR signal. COSTIMULATORYMOLECULESsuchas CD28 and CTLA-4 initiate their own intracellularsignals that enhance or modulate the TCR signal.Accessory molecules such as LFA-1 or CD2 provideadhesion at the cell contact site, strengthening theinteraction between the T cell and APC and allow-ing sustained signal transductions. The chainsof TCR are non-covalently associated with invariantchains of the CD3 complex (, , , and ) (Fig. 2).Intracellular parts of CD3 chains include one ormultiple immunoreceptor tyrosine-based activationmotifs (ITAMs). ITAMs provide sites of interaction

with protein tyrosine kinases (PTK) that propagatethe signaling events [16].Srcfamily PTKFynandLckphosphorylate ITAMs

upon TCR cross-linking by Ag/MHC, and fully phos-phorylated ITAMs recruit PTK ZAP-70 to the complexvia their SH2 domains. This allows LCK to transpho-

23Mechanisms of T cell activation

Treg

1. Inhibitory cytokines 2.Apoptosis

3. Metabolic disruption 4.Dendritic cells

Teff

Teff

Teff

T cell

cAMP

IL-10

TGF-

IL-35

CD25

IL-2

capture

Granzyme

IDO

IL-10

CD80CTLA4

FIGURE5. SEVERALMECHANISMSMEDIATETREGCELLFUNCTION1: Inhibitory cytokines such as IL-10 TGF-B and IL-35 can suppress T cell activation. 2: In some cases, cytolysis has

been described as a potential suppressive mechanism, killing effector cells in a granzyme A- and B-dependent fashion.

3: Cytokine deprivation, through binding of IL-2, leads to metabolic disruption of target cells or direct cAMP mediated

inhibition. 4: DC are targeted via direct cell-cell interactions, via CTLA4 (for example) or via suppressive cytokines

such as IL-10.

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sphorylate and to activate ZAP-70. The activatedZAP-70 interacts and phosphorylates SLP-76, and LAT.SLP-76 appears to be involved in actin cytoskeletonchanges, while LAT is a membrane-associated proteinthat upon phosphorylation provides binding sitesfor a number of critical signaling proteins, including

Grb2, Ras, and PLC-. PLC- plays a critical role inregulation of Ca2+ flux as it cleaves 4,5-biphosphate(PIP2) to diacylglycerol (DAG) and inositol 1,4,5-trip-phosphate (IP3) upon activation by PI3 kinase. DAGstimulates PKC, while accumulation of IP3 is the ini-tial trigger for release of intracellular Ca2+that, in turn,

triggers the opening of the plasma membrane Ca2+release-activated Ca2+ (CRAC) channels. Cascade ofthe signaling actions eventually results in activationof transcription factors including NF-AT, ELK-1, Jun,and ATF-2 and immune GENEEXPRESSION.

Although the first phosphorylation events occurwithin a few seconds of TCR cross-linking, the sus-tained contact and interaction of T cells with APC isrequired for full T LYMPHOCYTEactivation. Recent stud-ies of TCR engagement have focused on immuno-logical synapse (IS)-dynamic clustering of differentsurface molecules at the contact point between T cell

and APC involving TCR/CD3, co-RECEPTORS, and acces-sory molecules [17]. The latest studies of IS reporteda ring-type structure formed by TCR-Ag/MHC com-plexes around a cluster of LFA-1 and intercellularADHESION MOLECULE-1 (ICAM-1) followed by inver-sion of this structure, relocation of TCR/pMHC to thecenter, and formation of spatially segregated regionsof supramolecular activation complexes (SMAC)(Fig. 7). Mature IS contain central SMAC (c-SMAC),a cluster of TCR bound to Ag/MHC, and CD4 or CD8,CD3, CD2, CD2AP, CD28, PKC, and PTKLck. c-SMACis surrounded by peripheral SMAC, which containsLFA-1, ICAM-1, and talin. Thus, IS formed on the cellsurface may provide prolonged cellular interactionand sustained signaling leading to the Ca2+flux, actincytoskeleton reorganization, and full-blown T cellactivation. It was found that accumulation of cytolyticgranules in CTL is directed toward IS and that releaseof the granules takes place within p-SMAC.

Tolerance

An essential part of T CELL-MEDIATED IMMUNITY is thedevelopment of non-responsiveness toward naturallyoccurring self-Ag, while mounting effective immuneresponses against foreign Ag [18]. Breakdown ofself-TOLERANCE will result in the development ofAUTOIMMUNEDISEASES. Self-reactive T cells, both CD4+

24 T cell subsets and T cell-mediated immunity

FIGURE6. EFFECTIVET CELLACTIVATIONREQUIRESINTER-ACTIONWITHMULTIPLESURFACERECEPTORSONBOTHTCELLSANDAPCBinding of MHC class II peptide complex to the TCR and

CD4 induces signal 1 in the T cell. Positive costimula-

tion (signal 2) is provided by binding of CD80 or CD86

to CD28, whereas binding to CTLA4 will inhibit T cell

activation. Other interactions, such as binding of LFA-1

and ICAM-1, will ensure further intensified cell-cell

interactions. Binding of CD40 and CD40L will induce an

activating signal in the APC, enhancing the expression of

MHC molecules and costimulatory receptors.

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25Mechanisms of T cell activation

and CD8+, have been shown to be responsible for ini-tiating and mediating tissue damage in many experi-mental animal models of organ-specific AUTOIMMU-NITYas well as in human studies.

Immunological TOLERANCE is achieved by differ-ent mechanisms at different stages. Initially, potentialself-reactive T LYMPHOCYTESare deleted during T celldevelopment in the thymus. High-AFFINITY interac-tion of TCR on immature thymocytes with self-Ag onthymic stromal cells results in APOPTOSISand elimina-tion of such T cells in the process known as negativeselection. T cells with TCR of low to moderate AFFINI-TYto self-Ag escape from the thymus and migrate tothe periphery. These T cells are normally ignorant toself-Ag or develop TOLERANCEafter initial activation.

Although the Ag-specific TCRs of T cells do notpossess an intrinsic mechanism to distinguish selffrom non-self peptides, the activation by self-Agis different to that by foreign Ag, mainly due tothe absence of COSTIMULATORY SIGNALS from non-activated APC. This is in contrast to activated APC

that up-regulate COSTIMULATORY MOLECULES duringINFLAMMATION, infections, or other pathological con-ditions. Partial activation of T cells in the absence ofCOSTIMULATORYSIGNALSleads, instead of activation, tothe state of T cell unresponsiveness toward furtherstimulation, also known as anergy [19].

In most cases, COSTIMULATORY MOLECULES willdirect T cell response towards either activation orTOLERANCE. Simple absence of COSTIMULATORYSIGNALSwas shown to induce anergy in effector T cells invivoand in vitro, while nave T cells may require anegative signal of CTLA-4 engagement to developanergy and become tolerant.

Self-reactive cycling T cells may also undergo pro-grammed cell death after re-exposure to the same

Ag in a process called activation-induced cell death(AICD). AICD is mediated by death RECEPTORS(FAS/FAS-LIGANDinteraction of CD4+T cells and by TNFRII/TNF interaction of CD8+T cells) that involve interac-tion of caspase-dependent, death-inducing signalingcomplexes (DISC).

CD28

CD2

CD4

CD3

CD3

APCT cell

CD28

CD2

CD4CD3

APCT cell

TCR Ag/MHC

SMAC: Immature Mature

LFA-1 ICAM 1

LFA-1 ICAM 1TCR Ag/MHC

TCR Ag/MHC

TCR Ag/MHCLFA-1 ICAM 1

LFA-1 ICAM 1

FIGURE7. RECEPTORCLUSTERSOFSURFACEMOLECULESSchematic view of receptor clusters of different surface molecules forming a supramolecular activation complex

(SMAC) on the membrane of the T cell at the site of interaction with the APC. The SMAC changes during the activa-

tion process, inverting central and peripheral composition.

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27Selected readings

Fehervari Z, Sakaguchi S (2006) Peacekeepers of the

immune system.Sci Am 295: 5663

Shevach EM, Stephens GL (2006) The GITR-GITRL interac-

tion: co-stimulation or contrasuppression of regulatory

activity?Nat Rev Immunol6: 613618

Battaglia M, Gregori S, Bacchetta R, Roncarolo MG (2006)

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