Fas (CD95) expression and death-mediating function are induced by CD4 cross-linking on CD4(+) T cells

The CD4 receptor contributes to T-cell activation by coligating major histocompatibility complex class II on antigen presenting cells with the T-cell receptor (TCR)/CD3 complex, and triggering a cascade of signaling events including tyrosine phosphorylation of intracellular proteins, Paradoxically, CD4 cross-linking prior to TCR stimulation results in apoptotic cell death, as does injection of anti CD4 antibodies in vivo or CD4 ligation by HIV glcoprotein (gp) 120, In this report we investigate the mechanism by which CD4 cross-linking induces cell death, We have found that CD4 cross-linking results in a small but rapid increase in levels of cell surface Fas, a member of the tumor necrosis factor receptor family implicated in apoptotic death and maintenance of immune homeostasis. Importantly, CD4 crosslinking triggered the ability of Fas to function as a death molecule, Subsequent to CD4 cross-linking, CD4(+) splenocytes cultured overnight became sensitive to Fas-mediated death, Death was Fas-dependent, as demonstrated by cell survival in the absence of plate-bound anti-Fas antibody, and by the lack of CD4-induced death in cells from Fas-defective lymphoproliferative (lpr) mice, We demonstrate here that CD4 regulates the ability of Fas to induce cell death in CD4(+) T cells.