CD4 FUNCTION IN THYMOCYTE DIFFERENTIATION AND T-CELL ACTIVATION

The ectodomains of the T cell surface glycoproteins CD4 and CD8 bind t o membrane-proximal domains of MHC class II and class I molecules, res pectively, while both cytoplasmic domains interact with the protein ty rosine kinase (PTK) p56lck (lck) through a shared cysteine-containing motif. Function of CD4 and CD8 requires their binding to the same MHC molecule as that recognized by the T cell antigen receptor (TCR). In v itro studies indicate that CD4-associated lck functions even in the ab sence of kinase activity. In vivo experiments show that, whereas helpe r T cell development is impaired in CD4-deficient mice, high level exp ression of a transgenic CD4 that cannot bind lck rescues development o f this T cell subset. These studies suggest that CD4 is an adhesion mo lecule whose localization is regulated through protein-protein interac tions of the associated PTK and whose function is to increase the stab ility of the TCR signalling complex by binding to the relevant MHC. Th e function of CD4 in development has been further studied in the conte xt of how double positive (CD4+CD8+) thymocytes mature into either CD4 + T cells with helper function and TCR specificity for class II or int o CD8+ T cells with cytotoxic function and specificity for class I. St udies using CD4-transgenic mice indicate that development of single po sitive T cells involves stochastic downregulation of either CD4 or CD8 , coupled to activation of a cytotoxic or helper program, respectively , and subsequent selection based on the ability of the TCR and remaini ng coreceptor to engage the same MHC molecule.