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

Abstract

+ 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.immunology | T-cell receptor signaling | supported planar bilayers

Sequestosome1/p62: A regulator of redox-sensitive voltage-activated potassium channels, arterial remodeling, inflammation, and neurite outgrowth

“…The SQSTM1-Lck-Dlgh1-K v 1.3 signaling axis may be important in regulation of T cell activation, since K v 1.3, Dlgh1, and Lck translocate to the IS together with TCRs during activation of T cells, leading to cytokine production and proliferation of human CD4 + T cells [113]. Analysis of Dlgh1 gene-targeted mice shows that peripheral lymph node Dlgh1 -/-T cells exhibited enhanced proliferative response to TCR-induced stimulation, while thymic development was normal [114].…”

“…Since Lck is important in GATA-3 expression [110], we suggest a possible cooperation of SQSTM1 and Lck in GATA-3 expression and following cytokine secretion. In T lymphocytes, Lck links between K v 1.3 and CD4 on T cell activation [113]. CD4 interacts with other immune T cell receptors during activation [113].…”

Selective Phosphorylation of the Dlg1AB Variant Is Critical for TCR-Induced p38 Activation and Induction of Proinflammatory Cytokines in CD8+ T Cells

“…We and others have demonstrated that Dlg1 plays a vital role in T cell development, activation and effector responses utilizing Dlg1 knockdown and overexpression systems (4,5,7,9,10,16). However, initial knockout studies that ablate Dlg1 early in T cell development do not show striking functional differences, likely because of compensation from other Dlg1 family members (36,37).…”

“…We and others have demonstrated that Dlg1 specifies TCR signal transduction, by coordinating the activation of p38 through the alternative pathway (5,7,16). The alternative p38 pathway is initiated downstream of the TCR, and requires the activity of proximal tyrosine kinase Lck and Zap70 (17).…”

“…role in regulating CD4 + T cell development and function. In CD4 + regulatory T cells, Dlg1 expression and localization to the immune synapse correlates with p38 phosphorylation, NFATdependent transcription, and regulatory T cell-suppressive activity (16). In CD4 + effector cells, Dlg1 is thought to play a role in skewing toward expression of Th1 cytokines (36).…”