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

Zhiduo Liu, Michael Y. Gerner, Nicholas Van Panhuys, Andrew G. Levine, Alexander Y. Rudensky and Ronald N. Germain ()
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Zhiduo Liu: Lymphocyte Biology Section, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Michael Y. Gerner: Lymphocyte Biology Section, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Nicholas Van Panhuys: Lymphocyte Biology Section, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Andrew G. Levine: Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center
Alexander Y. Rudensky: Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center
Ronald N. Germain: Lymphocyte Biology Section, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health

Nature, 2015, vol. 528, issue 7581, 225-230

Abstract: Abstract 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.

Date: 2015
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DOI: 10.1038/nature16169

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