The Apoptotic Pathway Contributing to the Deletion of Naive CD8 T Cells during the Induction of Peripheral Tolerance to a Cross-Presented Self-Antigen

Abstract

The maintenance of T cell tolerance in the periphery proceeds through several mechanisms, including anergy, immuno-regulation, and deletion via apoptosis. We examined the mechanism underlying the induction of CD8 T cell peripheral tolerance to a self-Ag expressed on pancreatic islet β-cells. Following adoptive transfer, Ag-specific clone 4 T cells underwent deletion independently of extrinsic death receptors, including Fas, TNFR1, or TNFR2. Additional experiments revealed that the induction of clone 4 T cell apoptosis during peripheral tolerance occurred via an intrinsic death pathway that could be inhibited by overexpression of Bcl-2 or targeted deletion of the proapoptotic molecule, Bim, thereby resulting in accumulation of activated clone 4 T cells. Over-expression of Bcl-2 in clone 4 T cells promoted the development of effector function and insulitis whereas Bim−/− clone 4 cells were not autoaggressive. Examination of the upstream molecular mechanisms contributing to clone 4 T cell apoptosis revealed that it proceeded in a p53, E2F1, and E2F2-independent manner. Taken together, these data reveal that initiation of clone 4 T cell apoptosis during the induction of peripheral tolerance to a cross-presented self-Ag occurs through a Bcl-2-sensitive and at least partially Bim-dependent mechanism.

Contribution of TCR Signaling Strength to CD8+ T Cell Peripheral Tolerance Mechanisms

“…Upon day 30 virus recall we observed that low level (1 μg) cross-presentation of apoptotic cell-derived peptide lead to efficient deletion (Fig 6a), whereas cross-presentation of a high level of peptide (10 μg) failed to efficiently delete CL4 cells. We had previously shown deletional tolerance induced by peptide delivery in InsHA transgenic mice to be BIM-dependent (17). Here we confirmed that deletion of CL4 cells associated with low dose of cross-presented HA antigen was also BIM-dependent, as BIM deficient CL4 cells were not deleted (Fig.…”

The molecular signature of CD8+ T cells undergoing deletional tolerance

“…In addition, there was deletion-specific upregulation of the proapoptotic p53 target gene Perp (Table S3). This was surprising because peripheral deletion is p53 independent 29 and, as such, the relevance of this expression change to cell death is unclear.…”

Using Autoimmunity To Inform Tumor Immunity

“…In an elegant set of experiments, he and his colleagues demonstrated that Ag expressed in the islets was picked up by dendritic cells and cross-presented in the pancreatic lymph nodes (25). In our model, upon activation by such cross-presented Ag in the pancreatic lymph nodes, the Clone 4 cells underwent Bim-mediated apoptosis and never left the pancreatic lymph nodes (26). We also learned such tolerance was prevented by the presence of CD4 cells specific for HA, or by the presence of pathogens or inflammatory cytokines that activated the cross-presenting dendritic cells, which explained the difference between T cell tolerance and development of effector function (27).…”