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

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 TNFIRSF, 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-2Ralpha) and production of IL-2 and IFN-gamma 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