CCR4 is required for negative selection and suppression of Treg development by modulating interactions with and functions of thymic APCs 2234270

Abstract

Abstract Introduction Chemokine receptors play a critical role in guiding thymocytes into the medulla where they encounter antigen presenting cells displaying diverse self-antigens that induce central tolerance. Thymocytes expressing a T-cell receptor (TCR) with high affinity for these self-peptides undergo negative selection or become regulatory T cells (Tregs). We have shown that the chemokine receptors CCR4 and CCR7 promote the medullary accumulation and negative selection of distinct thymocyte subsets, raising the question of whether CCR4 and CCR7 have distinct impacts on thymocyte selection. Methods TCR repertoire analysis was carried out on newly generated CD4+ single positive (CD4SP) thymocytes and Treg, along with in vitro assays, imaging, and flow cytometric analyses of thymocytes from Ccr4 or Ccr7 deficient mice. Results These studies reveal a significant impact of CCR4, but not CCR7, on the CD4SP repertoire, identifying TCR clones that require CCR4 for negative selection. Notably, while CCR7 is necessary for selection of Treg TCRs, CCR4 inhibits selection of Treg TCRs, revealing opposite impacts of these chemokine receptors on the Treg repertoire. Thymocyte intrinsic expression of CCR4 does not account for impaired Treg selection. Instead, recirculating Tregs express CCR4, enabling close contact with thymic dendritic cells and suppression of new Treg selection. Conclusion Our work further clarifies the importance of CCR4 for negative selection and identifies a novel role for CCR4 in regulating Treg selection. Funding Source NIH/ NIAID R01AI104870 Topic Categories Hematopoiesis and Immune System Development (HEM)