Regulatory T (Treg) cells prevent autoimmunity by limiting immune responses and inflammation in the secondary lymphoid organs and nonlymphoid tissues. While unique subsets of Treg cells have been described in some nonlymphoid tissues, their relationship to Treg cells in secondary lymphoid organs and circulation remains unclear. Furthermore, it is possible that Treg cells from similar tissue types share largely similar properties. We have identified a short-lived effector Treg cell subset that expresses the α2 integrin, CD49b, and exhibits a unique tissue distribution, being abundant in peripheral blood, vasculature, skin, and skin-draining lymph nodes, but uncommon in the intestines and in viscera-draining lymph nodes. CD49b+ Treg cells, which display superior functionality revealed by in vitro and in vivo assays, appear to develop after multiple rounds of cell division and TCR-dependent activation. Accordingly, single-cell RNA-seq analysis placed these cells at the apex of the Treg developmental trajectory. These results shed light on the identity and development of a functionally potent subset of mature effector Treg cells that recirculate through and survey peripheral tissues.

Center of Life Sciences Skolkovo Institute of Science and Technology Moscow Russia

Central European Institute of Technology Masaryk University Brno Czech Republic

Department of Applied Physics and Applied Mathematics Columbia University New York NY

Howard Hughes Medical Institute Immunology Program and Ludwig Center Memorial Sloan Kettering Cancer Center New York NY

Privolzhsky Research Medical University Nizhny Novgorod Russia

Program for Computational and Systems Biology Memorial Sloan Kettering Cancer Center New York NY

Shemyakin Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences Moscow Russia

Single Cell Research Initiative Memorial Sloan Kettering Cancer Center New York NY

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Convergence, plasticity, and tissue residence of regulatory T cell response via TCR repertoire prism