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 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.
Department of Clinical and Experimental Medicine, Section of Pharmacology, Perugia University Medical School, Perugia, Italy.
Simona
S
Ronchetti
Department of Clinical and Experimental Medicine, Section of Pharmacology, Perugia University Medical School, Perugia, Italy.
Ornella
O
Zollo
Department of Clinical and Experimental Medicine, Section of Pharmacology, Perugia University Medical School, Perugia, Italy.
Stefano
S
Bruscoli
Department of Clinical and Experimental Medicine, Section of Pharmacology, Perugia University Medical School, Perugia, Italy.
Massimiliano
M
Agostini
Department of Clinical and Experimental Medicine, Section of Pharmacology, Perugia University Medical School, Perugia, Italy.
Rodolfo
R
Bianchini
Department of Clinical and Experimental Medicine, Section of Pharmacology, Perugia University Medical School, Perugia, Italy.
Giuseppe
G
Nocentini
Department of Clinical and Experimental Medicine, Section of Pharmacology, Perugia University Medical School, Perugia, Italy.
Emira
E
Ayroldi
Department of Clinical and Experimental Medicine, Section of Pharmacology, Perugia University Medical School, Perugia, Italy.
Carlo
C
Riccardi
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis; D017252:CD3 Complex / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D053450:Glucocorticoid-Induced TNFR-Related Protein; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D015375:Receptors, Interleukin-2 / Q000032:analysis; D017475:Receptors, Nerve Growth Factor / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology*
D000906:Antibodies; D017252:CD3 Complex; D016207:Cytokines; D053450:Glucocorticoid-Induced TNFR-Related Protein; D015375:Receptors, Interleukin-2; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C106544:Tnfrsf18 protein, mouse