Testing the contribution of ex-Tregs to autoimmunity and cancer immunity

PROJECT SUMMARY Insights into mechanisms of immune regulation have led to breakthroughs in treatments for cancer and autoimmune disease. Regulatory T cells (Tregs), an immunosuppressive subset of CD4+ T cells, are the ultimate immune regulators – acting as gatekeepers of immune responses, critically preventing autoimmune disease, but also hindering our body’s natural immunity toward cancer. While preclinical models have clearly shown that Treg suppression of immune responses against tumor cells can support cancer progression, the role of their counterparts, exTregs, is incompletely understood. ExTregs arise from Tregs but gain pro-inflammatory cytokine production and ultimately lose the expression of the master transcription factor of the Treg lineage, Foxp3. We hypothesize that exTregs are required to promote anti-cancer immunity and autoimmunity when Foxp3+ Tregs are depleted. Therefore, the activation of immune responses when immunosuppression by Tregs is lifted is critically initiated and promoted by exTregs, a novel mechanism to explain autoimmunity and anti-cancer immunity after Treg ablation. In this proposal, we will utilize a genetic Treg lineage tracing system to both monitor exTregs in situ as well as deplete Tregs alone (standard Treg ablation) or use a new genetic model to deplete both exTregs and Tregs simultaneously (DUAL ablation). Hence, we can test whether exTregs are required for tumor control or the onset of autoimmune disease when Tregs are depleted. Ultimately, our findings will be of great importance to understanding the impact of Treg ablation on the immune response and highlight the need for new strategies that target exTregs to ameliorate autoimmune toxicities or augment anti-cancer immune responses.