CD4 ENGAGEMENT INDUCES FAS ANTIGEN-DEPENDENT APOPTOSIS OF T-CELLS IN-VIVO

CD4 is a T lymphocyte receptor for major histocompatibility complex cl ass II antigens. It is referred to as coreceptor because it synergizes with the T cell receptor for antigen when both receptors become engag ed simultaneously. We show here in mice that when engaged by antibody independently of the T cell antigen receptor, CD4 induces T cells to u ndergo apoptosis. Several features of this process were identified. Th e expression of an intact Fas protein is a requirement for CD4-mediate d T cell death. Mice homozygous for the lpr mutation which are defecti ve in the expression of Fas and in their ability to delete lymphocytes apoptotically fail to delete anti-CD4-reactive T cells. Sessile anti- CD4-reactive T cells leave their homing environment in lymphoid organs and modulate their cell surface molecules, e.g. CD2, CD3, CD4. A mass ive influx of lymphoid cells with null-cell phenotype occurs in the bl ood where they begin to reexpress cell surface markers. With their arr ival in the circulation, anti-CD4-reactive T cells develop features of DNA degradation typical of apoptosis. More than one third of the circ ulating lymphoid cells show apoptotic features 7-8 h after anti-CD4 in jection. Their frequency declines subsequently presumably due to their physical disintegration via shedding of apoptotic bodies and phagocyt osis. Our data show that when not obliged to the activation process by the antigen receptor, CD4 can mediate deletion signals. Thus, besides functioning as coreceptor with the antigen receptor, CD4 has a functi on of its own in facilitating the induction of apoptosis.