Costimulatory signals

Induction of cell cycle progression requires the sustained activation of PTKs, PLC and the Ras pathway. The affinity of peptide/MHC ligand to TCR, and especially the off rate, has important consequences for the nature and duration of the transduced signal, as does the receipt of one or more costimulatory signals delivered by the interaction between accessory-receptors on the T cell and the antigen-presenting cell. Among the most well-studied of these acccssory receptors are CD2, CD4/8, CD28 and CD152 (CTLA4).

CD2 is a single-chain glycoprotein of 47-55 kDa that is expressed on thymocytes, all T cells and on large granular lymphocytes. It plays roles in T lymphocyte adhesion and in signal transduction. A physiologic ligand for the CD2 receptor is CD58 (LFA-3), a glycoprotein found on the surface of many hematopoietic and nonhematopoietic cells. Select pairs of monoclonal antibodies to CD2 have been shown to be capable of activating PTKs and PLC, and of inducing a proliferative response, suggesting either that CD2 might be an antigen-independent signal transduction molecule, or that CD2 amplifies the TCR-mediated signal. In mice, injections of CD2 antibody induce a state of antigen unresponsiveness.

CD4 and CD8 function in MHC-restricted antigen presentation by binding to invariant regions of the MHC molecules. CD4 and CD8 transmit signals important for T cell activation and growth via the associated protein tyrosine kinase, p56'*i. These coreceptor molecules provide an essential contribution for the TCR supramolecular complex (Figure 2). Recent studies suggest that the efficiency of CD4 recruitment to the TCR is a key factor in determining whether peptide-MHC complexes will display agonistic or antagonistic functions for CD4 cells.

The CD28 receptor family is the best understood of the costimulatory T cell receptors. CD28 is a 44 kDa homodimer and a member of the immunoglobulin gene family. It is an example of a hetero-philic cell adhesion complex, in which its cognate receptors are the ligands CD80 (B7-1) and CD86 (B7-2). CD28 appears to regulate a signal transduction pathway that is distinct from the TCR in some aspects and has a major role in the induction of cytokine secretion and the expression of the cell survival gene Bcl-xL. The CD28 cytoplasmic tail has no obvious enzymatic activity and unlike the TCR, it does not encode for ITAM motifs. The intracellular domain of CD28 does encode a (p)YXXM binding motif that can bind to the p85 regulatory subunit of phosphatidylinositol 3-kinase. It may be of clinical importance that CD28 signal transduction is resistant to a number of immunosuppressive agents. CD 152 (CTLA4) is related to CD28 and shares the same ligands, CD80 and CD86. However, the signal transduction pathways used by CTI.A4 appear to be distinct from CD28 and to primarily induce downre-gulation of T cell activation. In vivo, it is likely that CTLA4 has a major role in maintaining tolerance to self antigens.

CD154 (CD40L) is a type II membrane protein that is expressed on T cells. CD40I. is not constitut-ively expressed on T cells and expression is induced by TCR signals, and in some cases, by costimulatory signals. It appears that CD40L has a role as a master regulator of the immune system for both humoral and cellular immunity. The role of CD401. is to signal antigen-presenting cells. This occurs by ligation of CD40 on antigen-presenting cells and precedes upregulation of the CD28 ligands CD80/CD86 on the antigen-presenting cell.

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