Class I–restricted Cross-Presentation of Exogenous Self-Antigens Leads to Deletion of Autoreactive CD8⁺ T Cells

In this report, we show that cross-presentation of self-antigens can lead to the peripheral deletion of autoreactive CD8⁺ T cells. We had previously shown that transfer of ovalbumin (OVA)-specific CD8⁺ T cells (OT-I cells) into rat insulin promoter–membrane-bound form of OVA transgenic mice, which express the model autoantigen OVA in the proximal tubular cells of the kidneys, the β cells of the pancreas, the thymus, and the testis of male mice, led to the activation of OT-I cells in the draining lymph nodes. This was due to class I–restricted cross-presentation of exogenous OVA on a bone marrow–derived antigen presenting cell (APC) population. Here, we show that adoptively transferred or thymically derived OT-I cells activated by cross-presentation are deleted from the peripheral pool of recirculating lymphocytes. Such deletion only required antigen recognition on a bone marrow–derived population, suggesting that cells of the professional APC class may be tolerogenic under these circumstances. Our results provide a mechanism by which the immune system can induce CD8⁺ T cell tolerance to autoantigens that are expressed outside the recirculation pathway of naive T cells.