Engagement of glucocorticoid-induced TNF receptor costimulates NKT cell activation in vitro and in vivo.
Glucocorticoid-induced TNF receptor (GITR) is known to provide costimulatory signals to CD4+CD25- and CD4+CD25+ T cells during immune responses in vivo. However, the functional roles of GITR expressed on NKT cells have not been well characterized. In this study, we have explored the functions of GITR as a costimulatory factor on NKT cells. GITR was found to be constitutively expressed on NKT cells and its expression was enhanced by TCR signals. GITR engagement using DTA-1, an agonistic mAb against GITR, in the presence of TCR signals, augmented IL-2 production, the expression of activation markers, cell cycle progression, and the nuclear translocations of NF-kappaB p50 and p65. Furthermore, GITR engagement enhanced the production of IL-4, IL-10, IL-13, and IFN-gamma by NKT cells and the expression level of phosphorylated p65 in NKT cells in the presence of TCR engagement, indicating that GITR provides costimulatory signals to NKT cells. The costimulatory effects of GITR on NKT cells were comparable to those of CD28 in terms of cytokine production. Moreover, the coinjection of DTA-1 and alpha-galactosylceramide into B6 mice induced more IL-4 and IFN-gamma production than the coinjection of control mAbs and alpha-galactosylceramide. In addition, the adoptive transfer of DTA-1-pretreated NKT cells into CD1d(-/-) mice attenuated hypersensitivity pneumonitis more than control IgG pretreated NKT cells in these mice. These findings demonstrate that GITR engagement on NKT cells modulates immune responses in hypersensitivity pneumonitis in vivo. Taken together, our findings suggest that GITR engagement costimulates NKT cells and contributes to the regulation of immune-associated disease processes in vivo.
Kim
Hyun Jung
HJ
Department of Pathology and Graduate Program of Immunology, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, 110-799 Seoul, Korea.
Kim
Hye Young
HY
Kim
Byoung Kwon
BK
Kim
Sanghee
S
Chung
Doo Hyun
DH
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D018106:CD28 Antigens / Q000378:metabolism; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis; D005938:Glucocorticoids / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology*
D000911:Antibodies, Monoclonal; D018106:CD28 Antigens; D016207:Cytokines; D005938:Glucocorticoids; D018124:Receptors, Tumor Necrosis Factor