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J. Exp. Med.,
Volume 187, Number 5, March 2, 1998 711-720
By


From the * Department of Immunology and the 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.
Division of Infectious Diseases, Mayo Clinic,
Rochester, Minnesota 55905; and the § Department of Immunobiology, Immunex Corporation,
Seattle, Washington 98101
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