Fas (also known as Apo-1 and CD95) receptor has been suggested to control T cell expansion by triggering T cell-autonomous apoptosis. This paradigm is based on the extensive lymphoproliferation and systemic autoimmunity in mice and humans lacking Fas or its ligand. However, with systemic loss of Fas, it is unclear whether T cell-extrinsic mechanisms contribute to autoimmunity. We found that tissue-specific deletion of Fas in mouse antigen-presenting cells (APCs) was sufficient to cause systemic autoimmunity, implying that normally APCs are destroyed during immune responses via a Fas-mediated mechanism. Fas expression by APCs was increased by exposure to microbial stimuli. Analysis of mice with Fas loss restricted to T cells revealed that Fas indeed controls autoimmune T cells, but not T cells responding to strong antigenic stimulation. Thus, Fas-dependent elimination of APCs is a major regulatory mechanism curbing autoimmune responses and acts in concert with Fas-mediated regulation of chronically activated autoimmune T cells.

Apoptosis plays an essential role in T cell biology. Thymocytes expressing nonfunctional or autoreactive TCRs are eliminated by apoptosis during development. Apoptosis also leads to the deletion of expanded effector T cells during immune responses. The dysregulation of apoptosis in the immune system results in autoimmunity, tumorogenesis and immunodeficiency. Two major pathways lead to apoptosis: the intrinsic cell death pathway controlled by Bcl-2 family members and the extrinsic cell death pathway controlled by death receptor signaling. These two pathways work together to regulate T lymphocyte development and function.

Background Despite early antiretroviral therapy (ART), ART-suppressed people with HIV (PWH) remain at higher risk for infections and infection-related malignancies than the general population. The immunologic pathways that remain abnormal in this setting, potentially contributing to these complications, are unclear. Methods ART-suppressed PWH and HIV-negative controls, all CMV-seropositive and enriched for HIV risk factors, were sampled from an influenza vaccine responsiveness study. PWH were stratified by timing of ART initiation (within 6 months of infection [Early ART] vs. later) and nadir CD4 count among later initiators. Between-group differences in kynurenine/tryptophan (KT) ratio, IP-10, sCD14, sCD163, sTNFR2, IL-6, and suPAR were assessed after adjustment for confounders. Results Most participants (92%) were male, reflecting demographics of early ART initiators in San Francisco. Most biomarkers were higher among later ART initiators. Early ART participants achieved near-normal sTNFR2, IL-6, and suPAR levels, but substantially higher KT ratio than those without HIV after adjustment for confounders (P=0.008). sCD14, sCD163, and IP-10 followed a similar trend. Conclusions While early ART initiators restore near-normal levels of many inflammatory markers, the kynurenine pathway of tryptophan catabolism remains abnormally high. As this pathway confers adaptive immune defects and predicts tuberculosis and cancer progression, this pathway may contribute to persistent risks of these complications in this setting.