Scaffold protein Disc-Large Homolog 1 is required for T cell receptor-induced activation of regulatory T cell function (121.14)

Abstract

Abstract Foxp3+CD4+CD25high regulatory T cell (Treg) suppression of inflammation depends on T cell receptor (TCR)-mediated NFAT activation with reduced Akt activity. We investigated the role of the scaffold protein Dlgh1 in linking the TCR to this unique signaling outcome. The Treg immunological synapse (IS) recruited 4-fold more Dlgh1 than conventional CD4+ T cell IS. Tregs isolated from patients with active rheumatoid arthritis, or treated with tumor necrosis factor-α, display reduced function and diminished Dlgh1 recruitment to the IS. Furthermore, Dlgh1 silencing abrogated Treg function, impaired NFATc1 activation, reduced PTEN levels and increased Akt activation. Dlgh1 operates independently of the negative feedback pathway mediated by the related adapter protein Carma-1 and thus presents an array of novel targets to selectively manipulate Treg function.