Natural killer T cells accelerate atherogenesis in mice

Abstract

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...

Natural Killer T Cells Are Involved in Adipose Tissues Inflammation and Glucose Intolerance in Diet-Induced Obese Mice

“…27 We have demonstrated that NKT cells may be important in the evolution of atherosclerotic lesions by communicating macrophages through cell-cell interactions and/or secreting inflammatory cytokines. 10 Some of the inflammatory processes involved in atherogenesis (as shown in our previous study) resemble adipose tissue inflammation in the present study. Therefore, NKT cells are considered to mediate chronic inflammation in vascular and adipose tissues and can represent a direct and common soil for the development of atherosclerotic cardiovascular disease and diabetes.…”

“…8 These lymphocytes are mainly CD4-positive lymphocytes that express proinflammatory T H 1 cytokines, such as IFN-␥, and orchestrate the inflammatory response in the vascular wall by activating other cells. Previous studies, 9,10 including our own studies, demonstrated that NKT cells were present in atherosclerotic lesions and are critically important in atherogenesis. These findings suggest that NKT cells can also be involved in inflammation within adipose tissue.…”

MICA/B expression in macrophage foam cells infiltrating atherosclerotic plaques

“…Thioglycolate-elicited macrophages pulsed with oxidized LDL express elevated levels of CD1d and induce interferon-γ production by NKT cells (Nakai et al, 2004). CD8 + T cells also promote the development of atherosclerotic plaques by perforin-and granzyme B-mediated apoptosis of macrophages and tumor necrosis factor α-mediated inflammation (Kyaw et al, 2013).…”

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

“…After 2 h, spleens were removed and single cell suspensions were prepared. Splenocytes were suspended in RPMI-1640 supplemented with 10% fetal calf serum, 100 U/ml penicillin, 100 μg/ml streptomycin and 5x10 -5 M 2-mercaptoethanol (culture medium) and cultured in 24-well plates at 5x10 6 cells/ml for 90 min (23). Culture supernatants were harvested and quantified for IL-4 and IFN-Á using mouse IL-4 and IFN-Á enzyme-linked immunosorbent assay (ELISA) sets (Biosource) according to the manufacturer's protocol.…”

“…Propidium iodide (Sigma, St. Louis, MO) positive cells were electronically gated out from the analysis. The stained cells were analyzed on a FACScalibur flow cytometer (Becton-Dickinson, Mountain View, CA) with CellQuest software as described elsewhere (23).…”