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, CD3 cross-linking prior to TCR stimulation results in apoptotic cell death, as does injection of anti-CD4 antibodies in vivo of CD4 ligation by HIV glycoprotein (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 cross-linking 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.
Desbarats
J
J
Division of Basic Immunology, National Jewish Center for Immunology and Respiratory Medicine, Denver, CO 80206, USA.
Freed
J H
JH
Campbell
P A
PA
Newell
M K
MK
D000818:Animals; D017209:Apoptosis; D015704:CD4 Antigens / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology*; D002478:Cells, Cultured; D005260:Female; D015658:HIV Infections / Q000276:immunology; D051379:Mice; D008809:Mice, Inbred C3H; D019463:Mice, Inbred MRL lpr / Q000276:immunology*; D011940:Receptor Aggregation; D013154:Spleen / Q000166:cytology; D016176:T-Lymphocyte Subsets / Q000166:cytology*; D018417:Th1 Cells / Q000276:immunology; D015854:Up-Regulation; D019014:fas Receptor / Q000378:metabolism*
D015704:CD4 Antigens; D019014:fas Receptor