Role of glucocorticoid-induced TNF receptor family gene (GITR) in collagen-induced arthritis

In rheumatoid arthritis (RA), a widespread autoimmune/ inflammatory joint disease, early activation of effector CD4+ T lymphocytes, and cytokine production is followed by recruitment of other inflammatory cells, production of a range of inflammation mediators, tissue damage, and disease. GITR (glucocorticoid- induced TNFR family- related gene), a costimulatory molecule for T lymphocytes, increases CD4+ CD25- effector T cell activation while inhibiting suppressor activity of CD4+ CD25- T regulatory (Treg) cells. We analyzed the role of GITR in type II collagen (CII) - induced arthritis (CIA) using GITR -/- and GITR+/+ mice. Results indicate significantly less CIA induction in GITR+/+ mice than in GITR+/+ mice, with marked differences in erythema, edema, neutrophil infiltration, joint injury, and bone erosion. Production of IFN gamma, IL-6, TNF alpha, MIP-1 alpha, and MIP-2, inducible NOS (iNOS), COX-2, and nitrotyrosine poly-ADP-ribose (PAR) were also less in CII-treated GITR+/+ mice. Although CD4+ CD25+ Treg cells from GITR-/- and GITR-/- CII- challenged mice exerted similar suppressor activity in vitro, GITR triggering abrogated GITR+/+ Treg suppressor activity and costimulated CD4+ CD25- GITR+/+ effector cells. Furthermore, Treg cells from GITR-/- protected more than Treg cells from GITR+/+ mice against CIA when cotransferred with Treg-depleted splenocytes from arthritic GITR+/+ animals into severe combined immunodeficient (SCID) mice. In conclusion, GITR plays a critical role in the immunological response against CII and in the development of CIA.