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

• Published in: European journal of immunology 2004-03, Vol.34 (3), p.613-622
• Main Authors: Ronchetti, Simona, Zollo, Ornella, Bruscoli, Stefano, Agostini, Massimiliano, Bianchini, Rodolfo, Nocentini, Giuseppe, Ayroldi, Emira, Riccardi, Carlo
• Format: Article
• Language: English
• Subjects: Costimulation; T cell activation; Tumor necrosis factor receptor superfamily
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.200324804

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‐2Rα) and production of IL‐2 and IFN‐γ 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.