Cross-Activation of Regulatory T Cells by Self Antigens Limits Self-Reactive and Activated CD8⁺ T Cell Responses

The interaction between regulatory T (Treg) cells and self-reactive T cells is a crucial mechanism for maintaining immune tolerance. In this study, we investigated the cross-activation of Treg cells by self-antigens and its impact on self-reactive CD8⁺ T cell responses, with a focus on the P53 signaling pathway. We discovered that major histocompatibility complex (MHC) I-restricted self-peptides not only activated CD8⁺ T cells but also induced the delayed proliferation of Treg cells. Following HLA-A*0201-restricted Melan-A-specific (pMelan) CD8⁺ T cells, we observed the direct expansion of Treg cells and concurrent suppression of pMelan⁺CD8⁺ T cell proliferation upon stimulation with Melan-A peptide. Transcriptome analysis revealed no significant alterations in specific signaling pathways in pMelan⁺CD8⁺ T cells that were co-cultured with activated Treg cells. However, there was a noticeable upregulation of genes involved in P53 accumulation, a critical regulator of cell survival and apoptosis. Consistent with such observation, the blockade of P53 induced a continuous proliferation of pMelan⁺CD8⁺ T cells. The concurrent stimulation of Treg cells through self-reactive TCRs by self-antigens provides insights into the immune system's ability to control activated self-reactive CD8⁺ T cells as part of peripheral tolerance, highlighting the intricate interplay between Treg cells and CD8⁺ T cells and implicating therapeutic interventions in autoimmune diseases and cancer immunotherapy.