4-1BB engagement costimulates NKT cell activation and exacerbates NKT cell ligand-induced airway hyperresponsiveness and inflammation.
Multiple studies have demonstrated that 4-1BB (CD137), a member of the TNF receptor superfamily, is expressed on several immune cells including activated T cells. However, the expression and the role of 4-1BB on natural killer T (NKT) cells have not been fully characterized. In this study, it was shown that 4-1BB was not expressed on naive NKT cells but was rapidly induced on activated NKT cells by TCR engagement with alpha-galactosylceramide (alpha-GalCer). Also, 4-1BB signaling provided by 3H3, an agonistic anti-4-1BB mAb, promoted NKT cell activation resulting in enhanced cytokine production of NKT cells driven by alpha-GalCer. When NKT cell-driven airway immune responses were evaluated by intranasal administration of alpha-GalCer, airway hyperresponsiveness (AHR) and lung inflammation were significantly more aggravated in mice treated with 3H3 and alpha-GalCer than in mice treated with alpha-GalCer alone. These aggravations were accompanied by up-regulation of IL-4, IL-13, and IFN-gamma production. Interestingly, AHR was not developed in IL-4Ralpha-deficient mice treated with alpha-GalCer with or without 3H3 but was exacerbated in IFN-gamma-deficient mice. Our study suggests that 4-1BB on NKT cells functions as a costimulatory molecule and exacerbates the induction of NKT cell-mediated AHR, which is dependent on the IL-4Ralpha-mediated pathway.
Kim
Dong-Hyeon
DH
Laboratory of Immunology and Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Shillim-9-dong, Kwanak-gu, Seoul, Republic of Korea.
Chang
Woo-Sung
WS
Lee
Yoon-Sook
YS
Lee
Kyoo-A
KA
Kim
Yoon-Keun
YK
Kwon
Byoung S
BS
Kang
Chang-Yuil
CY
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D016535:Bronchial Hyperreactivity / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D005260:Female; D018836:Inflammation Mediators / Q000819:agonists / Q000276:immunology / Q000378:metabolism* / Q000502:physiology; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011956:Receptors, Cell Surface / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000819:agonists / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D053662:Interleukin-4 Receptor alpha Subunit
D000911:Antibodies, Monoclonal; D018836:Inflammation Mediators; D008024:Ligands; D011956:Receptors, Cell Surface; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; C504002:Il4ra protein, mouse; D053662:Interleukin-4 Receptor alpha Subunit