The CD2 molecule on T cells is also involved in T cellactivation, in conjunction with the TCR. CD2 is areceptor for LFA-3 (CD58), which is widely distributedon cells and is present on all APCs. In rodents CD48 bindsto CD2 and appears to be functionally equivalent to LFA-3 in humans. Both CD2 and LFA-3 are members of theimmunoglobulin superfamily.

Co-stimulation via B7 is a necessary signalfor T cell activation Resting T cells cannot respond optimally without co-stimulation via B7, and if they recognize their antigen in a non-stimulating manner they become inactivated, pro-ducing a state of immunological tolerance (Fig. 7.18).This tolerance is specific, only affecting TH cells thatrespond to a particular antigen. Persistent tolerancewithout cell death is known as clonal anergy.

As discussed in Chapters 2 and 12, many T cells aremade tolerant to self molecules during their developmentin the thymus. However, the process is not perfect andmany autoreactive T cells are present in the circulation.These cells may still be tolerized outside the thymusbecause, although they are specific for self MHCpeptide,this is often first encountered on cells that lack theappropriate co-stimulatory signals.

CD4 AND CD8 BINDING TO MHCMOLECULES INCREASE T CELL BINDINGAFFINITYCD4 and CD8 co-receptors for MHC molecules increasethe sensitivity of T cells to antigen-presenting moleculesby about 100-fold. The two major subsets of T cells, THand CTLs, express either CD4 or CD8, respectively.

CD4 and CD8 are only distantly related, but servesimilar functions as co-receptors for MHC moleculepeptideTCR interactions. In association with the MHCmoleculepeptideTCR complex: CD8 interacts with MHC class I molecules and consists

of two chains with immunoglobulin-like domains onlong stalks, coupled by a disulfide bridge;

CD4 interacts with MHC class II molecules andconsists of four immunoglobulin domains external tothe cell, and its cytoplasmic tail has a docking site forthe tyrosine kinase, Lck (see below);

CD8 co-receptor binds to conserved portions of the 3domains of class I molecules (see Fig. 5.6), leaving theportion enclosing peptide free to interact with the TCR.Like CD4, CD8 associates with Lck.

Both CD4 and CD8 co-receptors increase the sensi-tivity of T cells to antigen-presenting molecules by about100-fold.

THE HIGHLY ORDERED AREA OF CONTACTBETWEEN A T CELL AND AN APC IS ANIMMUNOLOGICAL SYNAPSEThe junction between a T cell and an APC does not justconsist of interacting molecules arranged randomly on the cell surfaces. There is a clustering of TCRs in a patch on the cell surface in an area of membrane withdistinct properties, surrounded by a ring of adhesionmolecules.

Immunological synapse formation is thought to be anactive dynamic process that helps T cells to distinguishpotential antigenic ligands.

Experiments show that initially TCR ligands are rele-gated to the outer ring of the nascent synapse. Subse-quently, there is transport of the complexes to a centralcluster, which is dependent, in an unknown way, onTCRligand interaction kinetics.

Productive T cell proliferation appears to depend on the formation of a stable central cluster of TCRsinteracting with MHC molecules (Fig. 7.19). The finalconfiguration of the synapse has MHC moleculepeptideTCR interactions at the hub of the synapseringed by ICAM-1LFA-1 interactions (Fig. 7.20). Large

7. ANTIGEN PRESENTATION

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Duel signaling is necessary for full T cell activation

Fig. 7.18 A T cell requires signals from both the TCR andCD28 for activation. Anergy in the absence of co-stimulatorymolecules inactivation or anergy results. This situation wouldprevail to tolerize T cells not removed by central tolerance toself antigens expressed on peripheral tissues. No effect in theabsence of an antigen-specific signal (e.g. wrong peptide)there is no effect on the T cell. Activation co-reception ofboth signals, from the surface of a professional APC, activatesthe T cell to produce IL-2 and its receptor (IL-2R). The celldivides and differentiates into an effector T cell, which nolonger requires signal 2 for its effector function.Downregulation at the termination of the immune response,CTLA-4 replaces CD28 and downregulates T cell function.

B7 CD28

B7 CTLA-4

T

T

T

T

T

IL-2R IL-2

APC

otherselfcell

MHC TCR

CD4/8

B7 CD28

CD28

no antigenTCRsignal

division, differentiationeffector functions

anergy

APC

activation

downregulation

no effect

APC