Frontline: GITR, a member of the TNF receptor superfamily, is costimulatory to mouse T lymphocyte subpopulations

Abstract

GITR (glucocorticoid-induced TNFR family related gene) is a member of the TNFR superfamily (TNFRSF) that is expressed in different cell types, including T lymphocytes. Because of a high homology in its cytoplasmic region with other known costimulatory members of the TNFRSF, we investigated whether GITR played a costimulatory role in T lymphocyte subpopulations. Our results show that the proliferation response of CD8 + and CD4 + peripheral T cell subpopulations was potentiated when a GITR costimulus was added to an anti-CD3 stimulus. Furthermore, expression of the main activation-induced receptor (IL-2R § ) and production of IL-2 and IFN-+ were increased more with a GITR costimulus than with anti-CD3 alone. GITR stimulation also enhanced anti-CD3-induced ERK phosphorylation, suggesting that GITR is involved in MAPK-pathway activation. Interestingly, CD4 + CD25 + regulatory T cell (Treg cell) proliferation was triggered by the GITR costimulus; Treg cell proliferation was paralleled by the loss of the anergic phenotype and suppressor activity. Nevertheless, unstimulated GITR -/-CD4 + CD25 + and GITR +/+ CD4 + CD25 + cells were equally able to exert suppressor activity on CD4 + CD25 -responder cells. These results indicate a novel function for GITR as costimulatory molecule of T cell subsets.

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

“…Significant differences at the 30:1 E/T ratio are indicated with xx (Po0.01). Level of cytotoxicity for sPSA DCs primed T cells against T2 cells pulsed with either PSA 51 or PSA 53 for all five donors are identical to controls (T cells primed with empty plasmid-transfected DCs). Prime (Table 1) and their cytotoxicity was tested against T2 cells pulsed with the same peptide that was used during boosting.…”

“…Purified CD4 þ CD25 þ T cells were added back at different time points following the initiation of the cultures (responder T cells/CD4 þ CD25 þ T-cell ratio ¼ 4:1). Responding cultures were then boosted twice with monocytes pulsed with one of three HLA-A2-restricted PSA-derived peptides (PSA 170 -squares; PSA 51 -triangles or PSA 53 -diamonds) and their cytotoxicity was tested against T2 cells pulsed with the same peptide that was used during boosting. Each point represents the mean and SD from three different experiments.…”

“…HLA A2( þ ) peripheral blood mononuclear cells that had been depleted of monocytes were primed with sPSA plasmid-transfected autologous dendritic cells that had (filled in symbols) or had not been (open symbols) transfected with the human GITR-L. Responding cultures were then boosted twice with monocytes pulsed with one of three HLA-A2-restricted PSA-derived peptides (PSA 170 -squares; PSA 51 -triangles or PSA 53 -diamonds) and their cytotoxicity was tested against T2 cells pulsed with the same peptide that was used during boosting. Each point represents the mean and SD from three different experiments.…”

“…Each point represents the mean and SD from three different experiments. Values for cytotoxicity of sPSA DCs-primed T cells against T2 targets pulsed with PSA 51 or PSA 53 peptides were compared (third column). Significant differences at the 30:1 E/T ratio are indicated with xx (Po0.01; reactivity against PSA 53 for donor B and PSA 51 or PSA 53 for donor C).…”

“…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.…”