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Donor Bone Marrow Type II (Non-V14J18 CD1d-Restricted) NKT Cells Suppress Graft-Versus-Host Disease by Producing IFN- and IL-4¹

Ji Hyung Kim^*,, Eun Young Choi and Doo Hyun Chung^2,*,,

^* Department of Pathology, Laboratory of Immune Regulation Graduate Program of Immunology, Cancer Research Institute, and Center for Animal Resource Development, Seoul National University College of Medicine, Seoul, South Korea

NKT cells in donor bone marrow (BM) have been demonstrated to protect against graft-vs-host disease (GVHD) following BM transplantation. Murine NKT cells are divided into two distinct subsets based on the invariant V14J18 TCR expression. However, details of the subset and mechanisms of the BM NKT cells involved in suppressing GVHD have not been clarified. Irradiated BALB/c or C3H/HeN mice administered B6 or J18^–/– BM cells show attenuation of GVHD, whereas recipients given CD1d^–/– BM cells did not show attenuation. Moreover, coinjection of BM non-V14J18 CD1d-restricted (type II) NKT cells and CD1d^–/– BM cells suppressed GVHD, whereas coinjection of BM V14J18 TCR (type I) NKT cells did not. These protective effects on GVHD depended upon IFN--producing type II NKT cells, which induced the apoptosis of donor T cells. The splenocytes of mice administered BM cells from B6.IL-4^–/– or J18^–/–IL-4^–/– mice produced lower levels of IL-4 and IL-10 than the splenocytes of mice transplanted with BM cells from B6, B6.IFN-^–/–, J18^–/–, or J18^–/–IFN-^–/– mice. Taken together, our results show that IFN--producing BM type II NKT cells suppress GVHD by inducing the apoptosis of donor T cells, while IL-4-producing BM type II NKT cells protect against GVHD by deviating the immune system toward a Th2-type response.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Korean Science and Engineering Foundation Grant R01-2001-000-00194-0 and Korean Ministry of Science and Technology Grant (M10422010004-04N2201-00410. J.H.K. was supported by the Seoul fellowship.

² Address correspondence and reprint requests to Dr. Doo Hyun Chung, Department of Pathology, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul, South Korea. E-mail address: doohyun{at}plaza.snu.ac.kr

³ Abbreviations used in this paper: GVHD, graft-vs-host disease; 7-AAD, 7-aminoactinomycin D; -GalCer, -galactosylceramide; BM, bone marrow; BMT, BM transplantation; cGy, centigray; GOT, glutamic-oxaloacetic transaminase; GPT, glutamic-pyruvic transaminase; Gy, gray; tg, transgenic.

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