CD4 Regulates Susceptibility to Fas ligand– and Tumor Necrosis Factor–mediated Apoptosis

Abstract

The current knowledge of CD4 function is limited to its role as a necessary coreceptor in TCR-initiated signaling. We have investigated whether CD4 regulates additional T cell functions. Using human primary resting CD4+ T cells, we demonstrate that CD4 activation is sufficient to induce lymphocyte death. Immediately after CD4 cross-linking, CD4+ T cells are rendered susceptible to apoptosis mediated by TNF or FasL. This, together with the concomitant induction of FasL within the same population, results in significant CD4+ T cell death in vitro. The CD4-dependent induction of susceptibility to apoptosis that is mediated by TNF or FasL is protein synthesis independent but phosphorylation dependent. After CD4 activation, PKC regulates susceptibility to apoptosis mediated by FasL but not the induction of susceptibility to TNF-dependent apoptosis. Moreover, significant differences between CD3 and CD4 activation were observed with regards to the kinetics of induction of CD4+ T cell susceptibility to FasL- and TNF-mediated apoptosis. Altogether, these results provide a model with which to study the molecular mechanisms regulating lymphocyte survival after CD4 activation, and highlight the potential role of CD4 in controlling lymphocyte apoptosis under physiological conditions or in disease states such as HIV infection.

A novel mechanism for HIV1-mediated bystander CD4+ T-cell death: neighboring dying cells drive the capacity of HIV1 to kill noncycling primary CD4+ T cells

“…[20][21][22][24][25][26] While our results confirm previous findings indicating that antibody-mediated engagement of CD4 or CXCR4 can indeed induce CD4 þ T-cell death, [27][28][29][30] they also indicate that the interactions of the HIV1 Env protein with CD4 and/or CXCR4 are not responsible for the killing by HIV1 particles of unstimulated, noncycling primary CD4 þ T cells. Rather, in the presence of cellular factors released by dying cells, CD4 þ T-cell killing required the presence of the Env protein on the viral particle simply because of a requirement for HIV1 postbinding fusion or entry into the CD4 þ T cells.…”

“…38 Both treatments prevented the capacity of HIV1 to induce CD4 þ T-cell death (Figure 1a), indicating that an interaction of the HIV1 Env with the CD4 cell-surface receptors was one of the events required for the induction of CD4 þ T-cell death. While the Leu3a antibody added in solution did not by itself affect CD4 þ T-cell survival (Figure 1a), CD4 receptor engagement by plateimmobilized Leu3a induced death in the same proportion of CD4 þ T cells as HIV1 (Figure 1a), consistent with previous reports, [27][28][29][30] and with the suggestion that HIV1 Env-mediated engagement of its CD4 cell-surface receptor may by itself cause CD4 þ T-cell death. [20][21][22]24 However, because CD4-specific antibodies may induce different cell signaling than HIV1 viral particles, we investigated whether HIV1-mediated CD4 þ T-cell death might rather be due to post-CD4-binding events.…”

“…3 Because most of the viral particles produced during HIV1 infection are replication-defective, 6 but can still bind to-, and enter into-CD4 þ T cells, viral proteins present at the surface or inside the viral particles have been proposed as candidates for the killing of noncycling CD4 þ T cells in the absence of productive infection of these cells. In vitro findings have suggested that among such viral proteins, the HIV1 surface envelope (Env) constitutes a major potential candidate for the HIV1-mediated killing of CD4 þ T cells in the absence of productive infection, 16,[20][21][22][23][24][25][26] through death signaling caused by engagement of either its cell-surface receptor, CD4 [27][28][29] or, for the Env of X4-tropic HIV1 strains, of its CXCR4 coreceptor. 25,26,30,31 Incubation of noncycling, primary CD4 þ T cells with X4-tropic HIV1 viral particles has been previously reported to cause CD4 þ T-cell death, after a delay of 3-4 days.…”

CD95/phosphorylated ezrin association underlies HIV-1 GP120/IL-2-induced susceptibility to CD95(APO-1/Fas)-mediated apoptosis of human resting CD4+T lymphocytes

“…[43][44][45][46] An ezrin-mediated CD95 connection to actin has a role in predisposing T lymphocytes to CD95-mediated GP120-induced CD95/ezrin association F Luciani et al apoptosis 43 and the CD95 connection to actin is a crucial requirement for the occurrence of the early events of the CD95 signaling. 44 However, there were no data supporting a possible role of this mechanism in the pathogenesis of CD95-mediated apoptosis of human diseases.…”

“…45 Hence, in order to verify whether a specific CD4 receptor triggering underlay the HIV-1 gp120-induced ezrin phosphorylation, ezrin/CD95 association and susceptibility to CD95-mediated apoptosis, we treated resting CD4 þ T cells with an anti-CD4 antibody, either alone or in combination with IL2, verifying whether this stimulation might mimic the gp120/IL2 effect.…”