CD4 REGULATES SUSCEPTIBILITY TO FAS LIGAND-MEDIATED AND TUMOR NECROSIS FACTOR-MEDIATED APOPTOSIS

The current knowledge of CD4 function is Limited to its role as a nece ssary coreceptor in TCR-initiated signaling. We have investigated whet her CD4 regulates additional T cell functions. Using human primary res ting 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 Fas t. This, together with the concomitant induction of FasL within the sa me population, results in significant CD4(+) T cell death in vitro. Th e CD4-dependent induction of susceptibility to apoptosis that is media ted by TNF or Fast is protein synthesis independent but phosphorylatio n dependent. After CD4 activation, PKC regulates susceptibility to apo ptosis mediated by Fast but not the induction of susceptibility to TNF -dependent apoptosis. Moreover, significant differences between CD3 an d CD4 activation were observed with regards to the kinetics of inducti on of CD4(+) T cell susceptibility to Fast-and TNF-mediated apoptosis. Altogether, these results provide a model with which to study the mol ecular mechanisms regulating lymphocyte survival after CD4 activation, and highlight the potential role of CD4 in controlling lymphocyte apo ptosis under physiological conditions or in disease states such as HIV infection.