FOXP3 + regulatory T cells (T reg cells) prevent autoimmunity by limiting the effector activity of T cells that have escaped thymic negative selection or peripheral inactivation. Despite the information available about molecular factors mediating the suppressive function of T reg cells, the relevant cellular events in intact tissues remain largely unexplored, and whether T reg cells prevent activation of self-specific T cells or primarily limit damage from such cells has not been determined. Here we use multiplex, quantitative imaging in mice to show that, within secondary lymphoid tissues, highly suppressive T reg cells expressing phosphorylated STAT5 exist in discrete clusters with rare IL-2-positive T cells that are activated by self-Antigens. This local IL-2 induction of STAT5 phosphorylation in T reg cells is part of a feedback circuit that limits further autoimmune responses. Inducible ablation of T cell receptor expression by T reg cells reduces their regulatory capacity and disrupts their localization in clusters, resulting in uncontrolled effector T cell responses. Our data thus reveal that autoreactive T cells are activated to cytokine production on a regular basis, with physically co-clustering T cell receptor-stimulated T reg cells responding in a negative feedback manner to suppress incipient autoimmunity and maintain immune homeostasis.
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