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

doi:10.1084/jem.187.5.711

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

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

By Alicia Algeciras,^* David H. Dockrell, David H. Lynch,^§ and Carlos V. Paya^*

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

The current knowledge of CD4 function is limited to its role as a necessary coreceptor in TCR-initiated signaling. We haveinvestigated whether CD4 regulates additional T cell functions.Using human primary resting CD4⁺ T cells, we demonstrate that CD4 activation is sufficient toinduce lymphocyte death. Immediately after CD4 cross-linking,CD4⁺ T cells are rendered susceptible to apoptosis mediated by TNFor FasL. This, together with the concomitant induction of FasLwithin the same population, results in significant CD4⁺ T cell death in vitro. The CD4-dependent induction of susceptibilityto apoptosis that is mediated by TNF or FasL is protein synthesisindependent but phosphorylation dependent. After CD4 activation,PKC regulates susceptibility to apoptosis mediated by FasL butnot the induction of susceptibility to TNF-dependent apoptosis.Moreover, significant differences between CD3 and CD4 activationwere 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 molecularmechanisms regulating lymphocyte survival after CD4 activation,and highlight the potential role of CD4 in controlling lymphocyteapoptosis under physiological conditions or in disease statessuch as HIV infection.

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