Mouse glucocorticoid-induced tumor necrosis factor receptor ligand is costimulatory for T cells

Abstract

Recently, agonist antibodies to glucocorticoid-induced tumor necrosis factor receptor (GITR) (tumor necrosis factor receptor superfamily 18) have been shown to neutralize the suppressive activity of CD4 ؉ CD25 ؉ regulatory T cells. It was anticipated that this would be the role of the physiological ligand. We have identified and expressed the gene for mouse GITR ligand and have confirmed that its interaction with GITR reverses suppression by CD4 ؉ CD25 ؉ T cells. It also, however, provides a costimulatory signal for the antigen-driven proliferation of naïve T cells and polarized T helper 1 and T helper 2 clones. RT-PCR and mAb staining revealed mouse GITR ligand expression in dendritic cells, macrophages, and B cells. Expression was controlled by the transcription factor NF-1 and potentially by alternative splicing of mRNA destabilization sequences.

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].…”

“…The administration of a-GITR mAb was previously shown to induce autoimmune manifestations in mice [48], and to abrogate Treg-mediated suppression of Teff activity in vitro [47,48]. 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].…”

Depletion of CD25+ cells from human T-cell enriched fraction eliminates immunodominance during priming with dendritic cells genetically modified to express a secreted protein

“…One way would be to look whether CD25 þ cell removal and CTLA-4 inhibition have a synergistic effect. A synergism of cytotoxic T lymphocyte-associated antigen 4 blockade Figure 7 CD4 þ CD25 þ T cells act early during priming to establish immunodominance to PSA 52 . HLA A2( þ ) peripheral blood mononuclear cells that had been depleted of monocytes and CD25 þ cells were primed with autologous dendritic cells transfected with the sPSA plasmid.…”

“…22,23,31,32 On the other hand, GITR-GITR-L interaction could also provide a costimulatory signal for the antigen-driven proliferation of naive T cells. 52,53 No matter what the mechanism is, GITR-L coexpression during gene-based vaccination may lead to enhancement of the immune response and alleviation of immunodominance. All of these results, however, have been obtained in an in vitro experimentation system.…”

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

“…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.…”