Apoptosis Regulators Bim and Fas Function Concurrently to Control Autoimmunity and CD8+ T Cell Contraction

Abstract

Throughout most of adult life, lymphocyte number remains constant because of a balance of proliferation and apoptosis. Mutation of Bim, a proapoptotic protein in the intrinsic death pathway, or Fas, a tumor necrosis factor receptor (TNFR) superfamily member of the extrinsic pathway, results in late-onset autoimmunity and increased antigen-specific CD8(+) T cell responses during viral infection. However, virus-specific immune responses eventually return to amounts comparable to those for nonmutant mice. Here, we show that loss of both Bim and Fas function resulted in a synergistic disruption of lymphoid homeostasis, rapid-onset autoimmunity, and organ-specific blocks on contraction of antiviral immune responses. When lymphocytic choriomeningitis virus (LCMV)-specific immune responses were quantitated, double-mutant mice had 100-fold more antigen-specific memory CD8(+) T cells in their lymph nodes than wild-type mice. Our results demonstrate that multiple death pathways function concurrently to prevent autoimmunity and downsize T cell responses.

CD70-Driven Costimulation Induces Survival or Fas-Mediated Apoptosis of T Cells Depending on Antigenic Load

“…6C). Interestingly, lpr 3 Bim 2/2 mice displayed a similar phenotype as lpr 3 CD70 Tg mice, as they also had strongly increased B220 + DN T cell numbers (11)(12)(13). The dramatic increase of B220 + DN T cells in lpr 3 CD70 Tg mice is consistent with a role for CD70 in the downregulation of Bim (see also Fig.…”

“…In contrast, in vitro and in vivo experiments using Fas-deficient lpr mice have shown that Fas induces apoptosis of activated T cells upon repetitive antigenic stimulation in a process called activationinduced cell death (9,10). More recently, using mice deficient for both Fas and Bim, several groups have shown that the intrinsic and extrinsic pathways cooperate to control the size of CD8 T cell responses during some but not all viral infection models (11)(12)(13). After HSV infection, contraction depends exclusively on Bim, whereas contraction after murine g-herpes virus infection requires both Fas-and Bim-dependent pathways.…”

Autophagy promotes T-cell survival through degradation of proteins of the cell death machinery

“…Addition of a pan-caspase inhibitor (zVAD) but not a Rip1 inhibitor (necrostatin 1) [21][22][23] was able to partially reverse cell death in Beclin 1-deficient T cells (Figure 5b), suggesting caspase-dependent apoptosis but not programmed necroptosis was involved in mediating the deleterious effect of autophagy inhibition. As caspase-independent cell death is mainly mediated by mitochondrion-mediated cell death pathway 21 in which Bim has a critical role, [24][25][26][27][28] we further studied the role of Bim in cell death by autophagy inhibition using T cells from BECN1/Bim double-deficient mice. Numbers of both CD4 þ and CD8 þ T cells were elevated in BECN1/Bim double-deficient mice compared with BECN1-deficient mice (Figure 5a).…”

Loss of the death receptor CD95 (Fas) expression by dendritic cells protects from a chronic viral infection

“…However, the attrition of T cells that normally follows the immune response was later attributed mostly to T-cell-intrinsic apoptotic pathways (22,23,36,37). In fact, animals with double deficiency of Fas and the proapoptotic molecule Bim (Bcl2l11) suffered a more severe autoimmune disease than mice deficient in Fas alone (38,39). In an attempt to dissect the role of different cell types in autoimmunity associated with Fas deficiency, we have shown that Fas deficiency restricted to APCs could induce the symptoms of systemic immunity (lymphoproliferation, enlargement of secondary lymphoid organs, foci of lymphopoesis in internal organs, and production of high titers of antinuclear antibodies) (9).…”