CD4 crosslinking primes resting CD4+ T lymphocytes to undergo Fas dependent apoptosis.
Int Conf AIDS 1996 Jul 7-12; 11:4 (abstract no. We.A.104) Algeciras A, Badley AD, Lynch DH, Paya CV; Mayo Clinic, Rochester, MN. Fax: 507-284-3757.
CD4 T lymphocyte depletion in HIV-infected individuals is associated with increased apoptosis of this lymphocyte subpopulation. Apoptosis of activated CD4 T cells is secondary to the interaction of Fas ligand (FasL) with Fas. Recent data indicates that CD4+ T cells from HIV-infected individuals are more susceptible to undergo apoptosis than CD4 cells from healthy donors when incubated with anti-Fas antibodies. The mechanism(s) which induce susceptibility to Fas-dependent apoptosis in the course of HIV infection remain unknown. To determine the mechanism(s) by which HIV infection primes CD4+ T lymphocytes to become Fas sensitive, we have focused on the role of the CD4 receptor. I) Monocyte depleted peripheral blood lymphocytes (PBLs) from healthy donors were CD4 crosslinked (CD4XL) by anti-CD4 monoclonal antibody (Leu-3a) or by HIV gp120 for 72 hours and treated with anti-Fas crosslinking antibodies, resulting in apoptosis. In addition, coincubation of PBLs with macrophages (recently shown to be a physiological source of Fas L) induces apoptosis in the CD4XL population which is blocked by anti-Fas blocking antibodies. II) Fas expression increases following CD4XL. To test whether Fas upregulation is responsible for the susceptibility to Fas-dependent apoptosis, Fas expression was analyzed at various time-points following CD4XL. While freshly isolated CD4+ T cells express Fas, CD4XL for 24 hours significantly upregulated Fas expression but did not correlate with increased sensitivity to Fas-dependent apoptosis. At 48 hours post CD4XL, Fas expression returned to pre CD4XL levels. However, at 72 hours, Fas expression was again significantly increased, and CD4 T cells have become susceptible to Fas-dependent apoptosis. III) CD4XL of CD4+ T cells induces TNF-alpha and IFN-gamma, which results in increased Fas expression. Addition of these two cytokines rendered CD4+ T lymphocytes susceptible to Fas-dependent apoptosis in a similar fashion than that observed with CD4XL. In conclusion, these studies demonstrate that CD4XL by either Leu 3a or gp120 is sufficient to render a resting naive CD4 T cell to become susceptible to Fas-dependent apoptosis. Cytokines such as TNF-alpha and IFN-gamma mimic CD4XL to achieve susceptibility to Fas-dependent apoptosis. Such susceptibility appears to be independent of the level of Fas surface expression on CD4 T cells. These findings suggest that CD4XL in vivo by free virus and by gp120-anti-gp120 immune complexes might be responsible for inducing susceptibility to Fas-dependent apoptosis.
Keywords: AEGIS, Antigens, CD95, CD4-Positive T-Lymphocytes, Apoptosis, Antigens, CD4, T-Lymphocytes, HIV Infections, Tumor Necrosis Factor, Antibodies, Monoclonal, Up-Regulation, Antibodies, Blocking, Fetal Alcohol Syndrome, Monocytes, Macrophages, genetics, ICA11
