NKT cells promote antibody-induced joint inflammation by suppressing transforming growth factor β1 production

Abstract

Although NKT cells has been known to exert protective roles in the development of autoimmune diseases, the functional roles of NKT cells in the downstream events of antibody-induced joint inflammation remain unknown. Thus, we explored the functional roles of NKT cells in antibody-induced arthritis using the K/BxN serum transfer model. NKT cell–deficient mice were resistant to the development of arthritis, and wild-type mice administrated with α-galactosyl ceramide, a potent NKT cell activator, aggravated arthritis. In CD1d−/− mice, transforming growth factor (TGF)-β1 was found to be elevated in joint tissues, and the blockade of TGF-β1 using neutralizing monoclonal antibodies restored arthritis. The administration of recombinant TGF-β1 into C57BL/6 mice reduced joint inflammation. Moreover, the adoptive transfer of NKT cells into CD1d−/− mice restored arthritis and reduced TGF-β1 production. In vitro assay demonstrated that interleukin (IL)-4 and interferon (IFN)-γ were involved in suppressing TGF-β1 production in joint cells. The adoptive transfer of NKT cells from IL-4−/− or IFN-γ−/− mice did not reverse arthritis and TGF-β1 production in CD1d−/− mice. In conclusion, NKT cells producing IL-4 and IFN-γ play a role in immune complex–induced joint inflammation by regulating TGF-β1.

Natural killer T cells ameliorate antibody-induced arthritis in macrophage migration inhibitory factor transgenic mice

“…Recently, it has been reported that NKT cells exacerbate mAb/LPS-induced joint inflammation in another Ab-mediated arthritis model, the K/BxN serum transfer model, through suppression of TGF-ß1 production (18). However, in our arthritis model no difference was noted in the serum TGF-ß levels between the ·-GalCer-treated and control groups of animals.…”

“…It has also been reported that NKT cells play protective roles in autoimmune diseases in human and mouse (15,16). However, in other reports, it has been suggested that NKT cells can promote inflammation in the same or similar arthritis model in mice (17,18). Thus, the role of NKT cells in arthritis remains controversial.…”

FTY720, a sphingosine 1-phosphate receptor modulator, inhibits CD1d-restricted NKT cells by suppressing cytokine production but not migration

“…3 On activation, NKT cells rapidly secret large amounts of IL-4 and IFN-g, which contribute to the regulation of innate and adaptive immune responses by NKT cells. 1,4 Therefore, NKT cells regulate various immune responses related to autoimmune diseases, hypersensitivity pneumonia, pulmonary fibrosis, oral tolerance, transplantation rejection, and graftversus-host disease. 1,[4][5][6][7][8][9][10] In addition, they enhance the immune response to tumors, microorganisms, and inflammation.…”

“…1,4 Therefore, NKT cells regulate various immune responses related to autoimmune diseases, hypersensitivity pneumonia, pulmonary fibrosis, oral tolerance, transplantation rejection, and graftversus-host disease. 1,[4][5][6][7][8][9][10] In addition, they enhance the immune response to tumors, microorganisms, and inflammation. 4,11,12 The results of a recent phase I clinical trial using Va24 NKT cells activated by a-galactosyl ceramide (a-GalCer) in patients with advanced and recurrent nonsmall-cell cancer 13 suggested that activating reagents for NKT cells may be good candidates for regulating immune disease.…”

CD4+CD25hi regulatory T‐cell frequency correlates with persistence of human papillomavirus type 16 and T helper cell responses in patients with cervical intraepithelial neoplasia

“…10 A functional role for iNKT in cancer and autoimmunity has been established in various animal models. [11][12][13][14][15] A role for iNKT cells in human disease is illustrated by reduced circulating iNKT cell numbers in patients suffering from autoimmune disease and cancer patients alike. 16,17 We have shown that circulating iNKT cell numbers remained low after tumor debulking 17 and that low pretreatment circulating iNKT cell numbers predict a poor clinical outcome in patients with head and neck squamous cell carcinoma (HNSCC).…”