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

Abstract

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.

Tolerization of Tumor-Specific T Cells Despite Efficient Initial Priming in a Primary Murine Model of Prostate Cancer

“…These data are consistent with the findings in other models that effector T cells can be tolerized when faced with persistent Ag (36,38,39). They are also consistent with another recent study demonstrating that administration of a peptide-pulsed DC vaccine up to 10 wk of age may prevent T cell tolerance and reduce tumor incidence in TRAMP mice (40).…”

“…It remains a possibility that, in the TRAMP model, tumorspecific T cells are programmed for deletion in the LNs and for tolerance in the prostate. Based on previous reports that demonstrate that low Ag levels lead to T cell deletion and high Ag levels lead to T cell tolerance (36), it could be argued that in the LNs of TRAMP mice, where Ag levels are low, T cells are programmed for deletion. Once T cells have reached the prostate, where Ag is constitutively being produced in high levels by the prostatic epithelium, T cell signaling could change and cells could be programmed for tolerance.…”

Tissue-Resident Memory CD8+ T Cells Can Be Deleted by Soluble, but Not Cross-Presented Antigen

“…Therefore, the cells are not inherently refractory to deletion by peptide. These data are consistent with results in which we found that multiple exposures to peptide were required to achieve total deletion of naive TCR transgenic CD8 T cells (35). In those studies, which examined deletion vs anergy of a homogeneous population of naive TCR transgenic CD8 cells, it was determined that a certain proportion of the cells were anergized rather than deleted as the result of exposure to a high concentration of cognate peptide.…”

Steady‐state antigen‐expressing dendritic cells terminate CD4+ memory T‐cell responses

“…peptide administration has been considered to constitute ''high-dose'' tolerance [30]. In various experimental systems, high antigen loads favor induction of unresponsiveness in CD8 1 T cells, both naïve and memory, whereas lower antigen loads favor deletion or induction of regulation [33,34], and our unpublished findings. It is possible that B cells being present in much larger numbers than DC provide a larger antigen ''source''.…”