Scaffold protein Disc large homolog 1 is required for T-cell receptor-induced activation of regulatory T-cell function.
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.
Molecular Pathogenesis Program, Department of Pathology, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY 10016, USA.
Alexandra
A
Zanin-Zhorov
Jiqiang
J
Lin
Jose
J
Scher
Sudha
S
Kumari
David
D
Blair
Keli L
KL
Hippen
Bruce R
BR
Blazar
Steven B
SB
Abramson
Juan J
JJ
Lafaille
Michael L
ML
Dustin
D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D015153:Blotting, Western; D000074288:Discs Large Homolog 1 Protein; D005434:Flow Cytometry; D006801:Humans; D008213:Lymphocyte Activation / Q000502:physiology*; D008565:Membrane Proteins; D008856:Microscopy, Fluorescence; D034622:RNA Interference; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D048868:Adaptor Proteins, Signal Transducing; C513314:DLG1 protein, human; D000074288:Discs Large Homolog 1 Protein; D008565:Membrane Proteins; D011948:Receptors, Antigen, T-Cell