Costimulation via Glucocorticoid-Induced TNF Receptor in Both Conventional and CD25+ Regulatory CD4+ T Cells

Abstract

The glucocorticoid-induced TNF receptor (GITR), which is a member of the TNF receptor family, is expressed preferentially at high levels on CD25+CD4+ regulatory T cells and plays a key role in the peripheral tolerance that is mediated by these cells. GITR is also expressed on conventional CD4+ and CD8+ T cells, and its expression is enhanced rapidly after activation. In this report we show that the GITR provides a potent costimulatory signal to both CD25+ and CD25− CD4+ T cells. GITR-mediated stimulation induced by anti-GITR mAb DTA-1 or GITR ligand transfectants efficiently augmented the proliferation of both CD25−CD4+ and CD25+CD4+ T cells under the limited dose of anti-CD3 stimulation. The augmentation of T cell activation was further confirmed by the enhanced cell cycle progression; early induction of the activation Ags, CD69 and CD25; cytokine production, such as IL-2, IFN-γ, IL-4, and IL-10; anti-CD3-induced redirected cytotoxicity; and intracellular signaling, assessed by translocation of NF-κB components. GITR costimulation showed a potent ability to produce high amounts of IL-10, which resulted in counter-regulation of the enhanced proliferative responses. Our results highlight evidence that GITR acts as a potent and unique costimulator for an early CD4+ T cell activation.

Inhibition of murine γδ lymphocyte expansion and effector function by regulatory αβ T cells is cell‐contact‐dependent and sensitive to GITR modulation

“…This was possibly due to GITR triggering rather than blocking, as the effect of the antibody was mimicked by GITR-L fusion proteins [46,50]. However, cross-linking of GITR was later shown to co-stimulate both Treg and Teff [50][51][52]. Therefore, the precise mechanistic involvement of GITR in Treg-mediated suppression remains under scrutiny [49].…”

An isoleucine-zipper motif enhances costimulation of human soluble trimeric GITR ligand

“…1,2 GITR is expressed constitutively on CD4 1 CD25 1 regulatory T cells at high levels, but it is also expressed on resting CD4 1 CD25 2 effector T cells at low levels and upregulated after activation. 3,4 In addition, expression of GITR is detected on natural killer cells and macrophages. 5,6 The natural GITRL is a type II transmembrane protein predominantly expressed on antigen-presenting cells, including dendritic cells, B cells, macrophages, endothelial cells and some tumor cells.…”

“…1, 2,5 Engagement of GITR and GITRL is correlated with the functional interplay among T cells, antigen-presenting cells and some tumor cells. GITR triggered by soluble GITRL, cell surface GITRL or anti-GITR monoclonal antibody (mAb) (DTA-1) abrogates regulatory Tcell suppression 3,4,7,8 and results in exacerbation of organ-specific autoimmune diseases, 3,9,10 , enhancement of antitumor immunity and the immunity to viral pathogens. [11][12][13] Thus, the functional interaction between GITR and GITRL is important for regulatory T cells to induce immune tolerance and regulate homeostasis.…”

Dendritic cells engineered to secrete anti-GITR antibodies are effective adjuvants to dendritic cell-based immunotherapy

“…13,14,21 An antibody that has been extensively tested in mice targets the glucocorticoid-induced tumor necrosis factor receptor (GITR). [22][23][24][25][26][27][28] GITR, a member of the tumor necrosis factor receptor superfamily, is constitutively expressed on Tregs but it is also expressed at low levels on multiple immune cells, including T cells, natural killer cells and B cells in which it is upregulated on activation. 7,23,[29][30][31] Treatment of mice with an agonistic anti-GITR mAb (anti-GITR), clone DTA-1, alone has been shown to cause exacerbated autoimmune disease in susceptible mice and enhanced anti-viral and anti-tumor immune responses in disease-bearing animals.…”

“…[22][23][24][25][26][27][28] GITR, a member of the tumor necrosis factor receptor superfamily, is constitutively expressed on Tregs but it is also expressed at low levels on multiple immune cells, including T cells, natural killer cells and B cells in which it is upregulated on activation. 7,23,[29][30][31] Treatment of mice with an agonistic anti-GITR mAb (anti-GITR), clone DTA-1, alone has been shown to cause exacerbated autoimmune disease in susceptible mice and enhanced anti-viral and anti-tumor immune responses in disease-bearing animals. 22,[24][25][26][27][28] When combined with DNA immunization against xenogeneic melanoma-related antigens, DTA-1-treated mice showed increased T-cell responses and protection from tumor challenge.…”