REPLACEMENT OF PRE-T CELL-RECEPTOR SIGNALING FUNCTIONS BY THE CD4 CORECEPTOR

An important checkpoint in early thymocyte development ensures that on ly thymocytes with an in-frame T cell receptor for antigen beta (TCR-b eta) gene rearrangement will continue to mature. Proper assembly of th e TCR-beta chain into the pre-TCR complex delivers signals through the src-family protein tyrosine kinase p56(kk) that stimulate thymocyte p roliferation and differentiation to the CD4(+)CD8(+) stage. However, t ile biochemical mechanisms governing p56(kk) activation remain poorly understood. In more mature thymocytes, p56(kk) is associated with the cytoplasmic domain of tile TCR coreceptors CD4 and CD8, and cross-link ing of CD3 leads to p56(kk) activation. To study the effect of synchro nously inducing p56(kk) activation in immature CD4(-)CD8(-) thymocytes , we generated mice expressing a CD4 transgene in Rag2(-/-) thymocytes . Remarkably, without further experimental manipulation, the CD4 trans gene drives maturation of Rag2(-/-) thymocytes in vivo. We show that t his process is dependent upon the ability of the CD4 transgene to bind Lck and on the expression of MHC class II molecules. Together these r esults indicate that binding of MHC class II molecules to CD4 can deli ver a biologically relevant, Lck-dependent activation signal to thymoc ytes in the absence of the TCR-alpha or -beta chain.