Scaffold protein Disc large homolog 1 is required for T-cell receptor-induced activation of regulatory T-cell function

Alexandra Zanin-Zhorov, Jiqiang Lin, Jose Scher, Sudha Kumari, David Blair, Keli L. Hippen, Bruce R. Blazar, Steven B. Abramson, Juan J. Lafaille, Michael L. Dustin

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

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 languageEnglish (US)
Pages (from-to)1625-1630
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number5
DOIs
StatePublished - Jan 31 2012

Keywords

  • Immunology
  • Supported planar bilayers
  • T-cell receptor signaling

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