Fatal interactions: fas-induced apoptosis of mature T cells

Abstract

Both immature cortical thymocytes and mature peripheral T cells may be induced to undergo apoptosis by ligation of the T cell antigen receptor (TCR). lntrathymic deletion is clearly an important mechanism by which the T cell system is rendered tolerant to many self-antigens, while the function of peripheral deletion is less clear. One possibility is that peripheral deletion is the mechanism that brings immune responses to a close after antigen has been cleared; another is that peripheral deletion is observed only with doses of antigen that are supraoptimal for inducing an effective T cell response; a third is that self-reactive T cells that evade clonal deletion in the thymus are subject to activation-induced deletion to maintain self-tolerance in the periphery. Peripheral T cell deletion could serve several or all of these functions. Distinct apoptosis mechanisms act during the deletion of immature and mature T cells. Overexpression of bcl-2 in transgenic mice has little effect on intrathymic clonal deletion, but inhibitssuperantigen-induced peripheral Tcell deletion(Sentman et al., 1991; Strasseret al., 1991). Now Singer and Abbas (1994 [this issue of Immuni~]) have shown a clear difference between intrathymic and peripheral T cell deletion in the requirement for the cell surface molecule Fas, also known as APO-l or CD95 In this paper, aT cell receptor transgenic mouse line has been crossed with the Ipr mutant, which does not express Fas due to a mutation in which insertion of a transposon disrupts the Fas gene (WatanabeFukunaga et al., 1992a). Injection of the specific antigenic peptide results in intrathymic and peripheral T cell deletion in TCR transgenic, but otherwise normal, animals; whereas in TCR transgenic Iprlpr homozygotes there is intrathymic but not peripheral deletion. This experiment knits together a number of previous studies in which different aspects of T cell deletion were characterized in Ipr mutant mice. Several groups have analyzed the endogenous superantigen-induced intrathymic clonal deletion of T cells expressing TCR Vj3 genes; in general, this form of deletion is not compromised by the Ipr mutation (Kotzin et al., 1988; Singer et al., 1989), although there is a clonal deletion defect due to genetic background abnormalities in MRL-lpr mice (Smyth et al., 1992). In Ipf-horn@ zygous TCR transgenic mice that expressed the anti-HYI Db TCR on CD8+ cells, male mice were able to delete the self-reactive thymocytes despite the lack of Fas (Zhou et al., 1991). In contrast, while injection of the exogenous superantigen staphylococca I enterotoxin B into normal mice results in transient T cell expansion followed by massive peripheral deletion, the same procedure in Ipr mutant mice lead to a sustained expansion without deletion (Scott et al., 1993). The Singer and Abbas paper shows that these differences are not contingent on the antigenic system, since both thyMinireview