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Foxp3(+)CD4(+)CD25(high) regulatory T cell (Treg) suppression of inflammation depends on T-cell receptor-mediated Nuclear Factor of Activated T cells c1 (NFATc1) activation with reduced Akt activity. We investigated the role of the scaffold protein Disc large homolog 1 (Dlgh1) in linking the T-cell receptor to this unique signaling outcome. The Treg immunological synapse (IS) recruited fourfold more Dlgh1 than conventional CD4(+) T-cell IS. Tregs isolated from patients with active rheumatoid arthritis, or treated with tumor necrosis factor-α, displayed reduced function and diminished Dlgh1 recruitment to the IS. Furthermore, Dlgh1 silencing abrogated Treg function, impaired NFATc1 activation, reduced phosphatase and tensin homolog levels, and increased Akt activation. Dlgh1 operates independently of the negative feedback pathway mediated by the related adapter protein Carma1 and thus presents an array of unique targets to selectively manipulate Treg function.

Original publication

DOI

10.1073/pnas.1110120109

Type

Journal article

Journal

Proceedings of the National Academy of Sciences of the United States of America

Publication Date

17/01/2012

Volume

109

Pages

1625 - 1630

Addresses

Molecular Pathogenesis Program, Department of Pathology, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY 10016, USA.

Keywords

Humans, Adaptor Proteins, Signal Transducing, Membrane Proteins, Receptors, Antigen, T-Cell, Microscopy, Fluorescence, Blotting, Western, Flow Cytometry, Lymphocyte Activation, RNA Interference, T-Lymphocytes, Regulatory