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Abstract

Due to the well-characterized role of Foxp3+ regulatory T cells (Tregs) in the regulation of immune responses to both self and foreign antigens, there has been significant interest in the clinical modulation of Tregs for the treatment of autoimmunity and cancer. Through T cell receptor (TCR) sequencing studies we demonstrate that the TCR repertoires of Tregs and CD4+ T conventional (Tconv) cells infiltrating genetically-driven murine prostate tumors are non-overlapping and we identified highly recurrent Treg clonotypes for further investigation. For one of the most highly recurrent prostate-tumor-associated Treg clonotypes, MJ23, we find that these cells are reactive to a prostate-associated antigen and they develop into Tregs in the thymus in an Aire-dependent manner. In the thymus, MJ23 Tregs require antigen presentation by CD11c+ dendritic cells (DCs) and develop in the absence of plasmacytoid and Batf3-dependent CD8a+ DCs. Furthermore, sequencing studies demonstrate that the thymic Treg repertoire is not impacted by the loss CD8a+ DCs. MJ23 Tregs enrich and become activated in the prostate-draining lymph nodes (pLNs) of prostate tumor-bearing and tumor-free male mice. We demonstrate that MJ23 Treg enrichment and activation in the pLNs occurs in an antigen-dependent manner and is lost in Ccr7-/- mice lacking migratory DCs (mDCs). Altogether, these results suggest that prostate tumors co-opt organ-specific, Aire-dependent, thymic-derived Tregs and that antigen presentation by CCR7-dependent mDCs orchestrates the localization and activation of these cells in the pLNs. These findings provide critical insights towards the mechanisms that modulate Treg development and homeostasis, and provide new avenues for future inquiry.

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