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: Animals; Antibodies - pharmacology; Apoptosis; CD3 Complex - immunology; CD4-Positive T-Lymphocytes - immunology; Cells, Cultured; Cytokines - metabolism; Glucocorticoid-Induced TNFR-Related Protein; Lymphocyte Activation; Mice; Mice, Knockout; Receptors, Interleukin-2 - analysis; Receptors, Nerve Growth Factor - genetics; Receptors, Nerve Growth Factor - immunology; Receptors, Nerve Growth Factor - physiology; Receptors, Tumor Necrosis Factor - genetics; Receptors, Tumor Necrosis Factor - immunology; Receptors, Tumor Necrosis Factor - physiology; Signal Transduction; T-Lymphocyte Subsets - immunology
• ISSN: 0014-2980
• 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-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.