Constitutive expression of Bcl-xL or Bcl-2 prevents peptide antigen-induced T cell deletion but does not influence T cell homeostasis after a viral infection

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.

Section: Cd8 T Cell Peripheral Tolerance Can Be Inhibited By Over-expsupporting

confidence: 93%

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

Redmond

Wei

Kreuwel

et al. 2008

“…It is possible a low level still persisted, but we favor the notion that they may have eventually died. This result would correlate with previous data on CD8 cells obtained from Bcl-x L transgenic mice in which Bcl-x L antagonized apoptosis of effector cells, but only delayed the contraction phase of an Ag-induced CD8 T cell response rather than preventing it (32). Recent results have suggested that recruitment of host cells is essential to the therapeutic action of adoptively transferred CD8 cells, rather than these cells directly targeting the tumor (27,33).…”

Section: Discussionmentioning

confidence: 99%

OX40 and Bcl-xL Promote the Persistence of CD8 T Cells to Recall Tumor-Associated Antigen

Song

Tang

Harms

et al. 2005

The molecular signals that allow primed CD8 T cells to persist and be effective are particularly important during cancer growth. With response to tumor-expressed Ag following adoptive T cell transfer, we show that CD8 effector cells deficient in OX40, a TNFR family member, could not mediate short-term tumor suppression. OX40 was required at two critical stages. The first was during CD8 priming in vitro, in which APC-transmitted OX40 signals endowed the ability to survive when adoptively transferred in vivo before tumor Ag encounter. The second was during the in vivo recall response of primed CD8 T cells, the stage in which OX40 contributed to the further survival and accumulation of T cells at the tumor site. The lack of OX40 costimulation was associated with reduced levels of Bcl-xL, and retroviral expression of Bcl-xL in tumor-reactive CD8 T cells conferred greatly enhanced tumor protection following adoptive transfer. These data demonstrate that OX40 and Bcl-xL can control survival of primed CD8 T cells and provide new insights into both regulation of CD8 immunity and control of tumors.

“…3A). These results are consistent with previous reports demonstrating that in the absence of proinflammatory signals, activation of naive CD8 T cells with soluble peptide can lead to significant levels of deletion (9,13,17,18,25,26). Tolerance induction with 10, 1, and 0.1 g doses of HA peptide also led to comparable deletion of the naive clone 4 T cells (Fig.…”

Section: Deletion Vs Anergy Of Peptide Tolerized Clone 4 T Cells In Vivomentioning

confidence: 99%

Distinct Requirements for Deletion versus Anergy during CD8 T Cell Peripheral Tolerance In Vivo

Redmond

Marincek

Sherman

2005

Activation of naive T cells by quiescent APCs results in tolerance through deletion and anergy. The underlying basis for these distinct fates is unclear. Using clone 4 TCR transgenic animals as a source of naive CD8 T cells, we examined the requirements for peripheral deletion in vivo. Our results demonstrate that independent of the amount of Ag used for stimulation, a single dose was insufficient to achieve complete clonal deletion. Instead, further antigenic exposure was required to completely eliminate all of the activated T cells. Additionally, consecutive stimulations with low doses of Ag were highly effective in promoting deletion. In contrast, although stimulation with high doses of Ag initially led to the apoptosis of many of the activated T cells, it induced hyporesponsiveness in a portion of the responding cells, thereby sparing them from further activation and deletion. These data explain why some conditions promote tolerance through clonal deletion whereas others promote anergy. Furthermore, these data provide a framework to devise protocols for effective deletion of potentially autoreactive T cells.