Abstract
Apaf1 is a critical component of the apoptosome and initiates apoptosis downstream mitochondrial damages. Although the importance of Apaf1 in embryonic development was shown, the role of Apaf1 in immune responses, especially T cell responses, has yet to be elucidated. We generated T cell-specific Apaf1-deficient mice (Lck-Cre-Apaf1f/f mice) and examined the antigen-specific delayed-type hypersensitivity (DTH). Lck-Cre-Apaf1f/f mice exhibited exacerbation of DTH responses as compared with Apaf1-sufficient control mice. In Lck-Cre-Apaf1f/f mice, antigen-specific T cells proliferated more, and produced more inflammatory cytokines than control T cells. Apaf1-deficient T cells from antigen-immunized mice showed higher percentages of activation phenotypes upon restimulation in vitro. Apaf1-deficient T cells from naive (non-immunized) mice also showed higher proliferation activity and cytokine production over control cells. The impact of Apaf1-deficiency in T cells, however, was not restored by a pan-caspase inhibitor, suggesting that the role of Apaf1 in T cell responses was caspase-independent/non-apoptotic. These data collectively demonstrated that Apaf1 is a negative regulator of T cell responses and implicated Apaf1 as a potential target for immunosuppressive drug discovery.
Highlights
Immune responses include activation and clonal expansion of relevant lymphocyte populations to wipe up invading foreign antigens
Genotypes of the mice were confirmed by Southern blot analysis of the genomic DNA using two external probes and a probe at exon 4 (Fig 1A) and Cre-driven successful ablation of Apaf1 in T cells and thymocytes were confirmed by Western blot analysis (Fig 1B)
Activated Lck-Cre-Apaf1f/f peripheral T cells were refractory to the mitochondria-dependent passive apoptosis induced by growth factor deprivation as compared with Apaf1-sufficient Apaf1f/f T cells (Fig 1D and S2 Fig); when lymph node (LN) T cells that had been previously activated with anti-CD3ε antibody plus anti-CD28 antibody were placed in new medium, in which T cell-derived IL-2 was insufficient, control Apaf1f/f T cells showed significant reduction in viability whereas Lck-Cre-Apaf1f/f T cells showed higher viability
Summary
Immune responses include activation and clonal expansion of relevant lymphocyte populations to wipe up invading foreign antigens. Once the antigens are removed, circulating activated lymphocytes, especially T cells, should be eliminated to avoid unnecessary inflammation and to maintain immune homeostasis, while only a few of the activated lymphocytes are fated to develop into memory lymphocytes. In this process, apoptosis plays critical roles[1]. Apoptosis in T cells can be initiated either extrinsically or intrinsically[2]. The extrinsic pathway is initiated by ligation of cell surface death receptors, including Fas[3].
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