Both osteopontin (OPN) and natural killer T (NKT) cells play a role in the development of immunological disorders. We examined a functional link between OPN and NKT cells. Concanavalin A (Con A)-induced hepatitis is a well-characterized murine model of T cell-mediated liver diseases. Here, we show that NKT cells secrete OPN, which augments NKT cell activation and triggers neutrophil infiltration and activation. Thus, OPN- and NKT cell-deficient mice were refractory to Con A-induced hepatitis. In addition, a neutralizing antibody specific for a cryptic epitope of OPN, exposed by thrombin cleavage, ameliorated hepatitis. These findings identify NKT cell-derived OPN as a novel target for the treatment of inflammatory liver diseases.

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In addition, repeated injections of ␣-GalCer or the related glycolipid OCH to apolipoprotein E knockout (apoE ؊/؊ ) mice during the early phase of atherosclerosis significantly enlarged the lesion areas compared with mice injected with vehicle control. However, administering ␣-GalCer to apoE ؊/؊ mice with established lesions did not significantly increase the lesion area but considerably decreased the collagen content. Atherosclerosis development in either AD-fed WT or apoE ؊/؊ mice was associated with the presence of V␣14J␣18 transcripts in the atherosclerotic arterial walls, indicating that NKT cells were recruited to these lesions. Thioglycolate-elicited macrophages pulsed with oxidized low-density lipoproteins expressed enhanced CD1d levels and induced NKT cells to produce interferon-␥, a potentially proatherogenic T-helper 1 (T H 1) cytokine. Collectively, we conclude that NKT cells are proatherogenic in mice. IntroductionAtherosclerosis is an inflammatory vascular disease that involves components of the innate and acquired immune systems. [1][2][3] Several studies have suggested that lymphocytes, which are detected in atherosclerotic lesions in humans and mice, 4,5 play a proatherogenic role. [6][7][8] Recently, the role of distinct lymphocyte subsets in the development of atherosclerosis has been evaluated. For example, emerging evidence indicates that T-helper 1 (T H 1) cells are proatherogenic, 9 whereas T H 2 cells are antiatherogenic. 10,11 These observations are further supported by the finding that T H 1 cytokines (eg,) are important in the progression of atherosclerosis [12][13][14][15] and that, among T H 2 cytokines, IL-10 is antiatherogenic. 16 On the other hand, recent studies have suggested that B cells play a protective role in atherogenesis. 17,18 Natural killer T (NKT) cells are a unique subset of lymphocytes that have surface markers and functions of T cells and NK cells. [19][20][21][22][23] Several characteristics of NKT cells suggest that they may play a role in the atherogenic process. Most NKT cells express an invariant V␣14J␣18 T-cell receptor (TCR)-V␣ chain paired with a restricted set of TCR-V␤ chains. These classical NKT cells recognize lipid antigens presented by the major histocompatibility complex (MHC) class 1-like molecule CD1d, produce copious amounts of IFN-␥ and IL-4 on activation, 22 and constitutively express Fas-ligand. 23 Moreover, NKT cells play a protective role in several autoimmune diseases, infections, and tumor progression/ metastasis. 20 Protective effects of NKT cells and their ligands in autoimmunity are largely attributed to their capacity to promote T H 2 immune responses. 24,25 However, in some situations, NKT cells can contribute to the development of T H 1 immune responses as well. 26 Therefore, it was difficult to predict whether NKT cells would play a proatherogenic or an antiatherogenic role. 2 To date, few studies have investigated the role of CD1d and CD1d-dependent T cells in atherogenesis. CD1d-expressing cells are present in human atherosclerotic...

CD4+8- or CD4-8+ thymocytes have been regarded as direct progenitors of peripheral T cells. However, recently, we have found a novel NK1.1+ subpopulation with skewed T cell antigen receptor (TcR) V beta family among heat-stable antigen negative (HSA-) CD4+8- thymocytes. In the present study, we show that these NK1.1+ CD4+8- thymocytes, which represent a different lineage from the major NK1.1- CD4+8- thymocytes or CD4+ lymph node T cells, vigorously secrete interleukin (IL)-4 and interferon (IFN)-gamma upon stimulation with immobilized anti-TcR-alpha beta antibody. On the other hand, neither NK1.1- CD4+8- thymocytes nor CD4+ lymph node T cells produced substantial amounts of these lymphokines. A similar pattern of lymphokine secretion was observed with the NK1.1+ CD4+T cells obtained from bone marrow. The present findings elucidate the recent observations that HSA- CD4+8- thymocytes secrete a variety of lymphokines including IFN-gamma, IL-4, IL-5 and IL-10 before the CD4+8- thymocytes are exported from thymus. Our evidence indicates that NK1.1+ CD4+8- thymocytes are totally responsible for the specific lymphokine secretions observed in the HSA- CD4+8- thymocytes.

Background-Macrophage and lymphocyte infiltration in adipose tissue may contribute to the pathogenesis of obesity-mediated metabolic disorders. Natural killer T (NKT) cells, which integrate proinflammatory cytokines, have been demonstrated in the atherosclerotic lesions and in visceral adipose tissue. Objective-To determine whether NKT cells are involved in glucose intolerance and adipose tissue inflammation in diet-induced obese mice. Methods and Results-To determine whether NKT cells are involved in the development of glucose intolerance, male ␤ 2 -microglobulin knockout (KO) mice lacking NKT cells and C57BL/6J (wild-type) mice were fed with a high-fat diet (HFD) for 13 weeks. Body weight and visceral obesity were comparable between wild-type and KO mice. However, macrophage infiltration was reduced in adipose tissue and glucose intolerance was significantly ameliorated in KO mice.To further confirm that NKT cells are involved in these abnormalities, ␣-galactosylceramide, 0.1 g/g body weight, which specifically activates NKT cells, was administered after 13 weeks of HFD feeding. ␣-Galactosylceramide significantly exacerbated glucose intolerance and macrophage infiltration as well as cytokine gene expression in adipose tissue. O besity, specifically visceral obesity, increases the risk for metabolic disorders, such as type 2 diabetes mellitus, dyslipidemia, and hypertension as well as atherosclerotic cardiovascular diseases. Previous studies have demonstrated that the accumulation of macrophages within adipose tissue is well documented in obese individuals and that adipose tissue inflammation plays an important role in the pathogenesis of these metabolic disorders. 1,2 Macrophages are attracted by chemokines, such as monocyte chemoattractant protein 1 (MCP-1), and contribute to local inflammation through the release of other inflammatory cytokines, such as tumor necrosis factor (TNF) ␣. In high-fat diet (HFD)-fed obese mice, it has been shown that infiltration of macrophages into adipose tissue coincides with the occurrence of obesitymediated metabolic disorders. 2 The important role of adipose tissue macrophages in the pathogenesis of metabolic disorders has further been supported by recent data in C-C motif chemokine receptor 2 (CCR2)-deficient mice. 3 The CCR2 Ϫ/Ϫ mice exhibited a reduction in adipose tissue macrophages in association with an improvement of glucose homeostasis and insulin sensitivity. However, the abolished monocyte and macrophage recruitment into peripheral tissue via interaction with MCP-1 could not completely inhibit HFD-mediated metabolic disorders, suggesting that other inflammatory cells may play a role in this context. Wu et al 4 and Rocha et al 5 demonstrated that CD3-positive T lymphocytes are present in human adipose tissue; and regulated upon activation, normal T cell expressed secreted (RANTES), a T-cell-specific chemokine, and its respective receptor CCR5 are expressed in adipose tissue from obese patients. However, the role of other types of lymphocytes in adipose tissue inflam...