It is believed that the encounter between a TCR and its antigen involves a low-affinity interaction. T cells have circumvented this problem by making use of coreceptors. In the case of a T cell that expresses a TCR recognizing antigenic peptides in the groove of a class II MHC molecule, this coreceptor function is fulfilled by CD4. If the TCR recognizes a class I MHC molecule, the coreceptor is CD8. By acting synergistically with the TCR, the coreceptors induce signal transduction events at low levels of receptor occupancy. T cells that go through maturation steps in the thymus are bipotential and can differentiate either along the CD4+ (helper) pathway or the CD8 (cytotoxic) pathway.

Early work addressing the role of the CD4 coreceptor in thymocyte differentiation made use of monoclonal antibodies specifically directed towards CD4. Although most of these experiments were instrumental in describing the coreceptor and/or cosignaling functions of CD4, they are at odds with more contemporary data using mouse lines containing either disrupted genes or transgenes. Indeed, the latter models have generated good evidence that thymocyte commitment is a stochastic event. It follows that no distinct TCR-mediated signals are required in this choice. This is consistent with experiments in which a mutated molecule of CD4 (tailless), incapable of binding p56lck, can rescue T helper development in a CD4_/_ mouse line. Therefore, in the context of thymic selection, the role of CD4 in the coreceptor-mediated TCR signaling is one of stabilization of the TCR-MHC interaction. In mice deficient for CD4 coreceptor expression, 90% of peripheral a/STCR' T cells are CDS '. These CD4 ' mice have been used to show that the human CD4 molecule can substitute for its murine counterpart. Interestingly, the requirement for CD4 in superanti-gen-mediated negative selection of specific V/3 seems to be differential and inversely proportional to the avidity of some Vj8 for Mis. That is, Mis 1A' -CD4 ' animals, thymocytes expressing V/36, V/38.1 and V/39 are deleted as in normal animals, while Vj87* thymocytes are not, reflecting the low avidity of V/37 for MlslA. These cells might require CD4 coreceptor-mediated stabilization of binding or signaling for clonal deletion. T helper activity and most class II-restricted T cell responses are also virtually absent in the periphery of these animals. For example, antibody titers are diminished 100-fold when these animals are immunized with T cell-dependent antigens. Moreover, these animals fail to mount an allo-response.

See also: CD3; CD8; CD45 (the leukocyte common antigen); Thymic epithelium: potential role in regulatory T cell tolerance; H2 class II; HLA class II; T cell receptor, ap; T cell receptor, 78; T lymphocyte activation; T lymphocyte differentiation.

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