Immune homeostasis enforced by co-localized effector and regulatory T cells

FOXP3+ regulatory T cells (Treg 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 Treg cells, the relevant cellular events in intact tissues remain largely unexplored, and whether Treg 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 Treg 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 Treg cells is part of a feedback circuit that limits further autoimmune responses. Inducible ablation of T cell receptor expression by Treg 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 Treg cells responding in a negative feedback manner to suppress incipient autoimmunity and maintain immune homeostasis. Autoantigen-presenting dendritic cells are shown to interact with both effector and regulatory T cells, and effector-produced IL-2 activates the transcription factor STAT5 in regulatory T cells, which in turn upregulates suppressive molecules and prevents autoimmunity. Regulatory T cells (Treg cells) limit the autoimmune response by suppressing autoreactive effector T cells in lymphoid organs under non-inflammatory conditions in an interleukin 2 (IL-2)-dependent manner. Using a novel tissue imaging technique termed histo-cytometry, Ronald Germain and colleagues identify highly suppressive Treg cells expressing the transcription factor STAT5 in its active phosphorylated state that exist in discrete clusters with rare IL-2+ T cells activated by self-antigens. Autoantigen-presenting dendritic cells are shown to interact with both effector and regulatory T cells. These mechanisms combine to upregulate suppressive molecules, thereby preventing autoimmunity.