Activation of natural killer T cells by α-galactosylceramide treatment prevents the onset and recurrence of autoimmune Type 1 diabetes

Sharif, Shayan; Arreaza, Guillermo; Zucker, Peter; Mi, Qing‐Sheng; Sondhi, Jitin; Naidenko, Olga V.; Kronenberg, Mitchell; Koezuka, Yasuhiko; Delovitch, Terry L.; Gombert, Jean‐Marc; Leite‐de‐Moraes, Maria; Gouarin, Christine; Zhu, Rong; Hameg, Agathe; Nakayama, Toshinori; Taniguchi, Masaru; Lepault, Françoise; Lehuen, Agnès; Bach, Jean‐François; Herbelin, André

doi:10.1038/nm0901-1057

Cited by 582 publications

(555 citation statements)

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“…A similar protection was observed after specific iNKT cell stimulation with exogenous ligands, a-galactosylceramide (a-GalCer) and its analogues [8][9][10][11]. Early reports suggested that iNKT cell protection was associated with the induction of a Th2 response to islet autoantigens [8,[10][11][12]. However, following studies using the transfer of anti-islet T cells showed that iNKT cells inhibit the differentiation of these auto-reactive T cells into effector cells during their priming in pancreatic lymph nodes (PLNs) [13,14].…”

Section: Introductionsupporting

confidence: 55%

“…iNKT cells are reduced in number in diabetes-prone NOD mice [4,5], and increasing the number of iNKT cells by adoptive transfer [6,7] or via the introduction of a Va14-Ja18 transgene, reduces significantly the progression of the disease [6]. A similar protection was observed after specific iNKT cell stimulation with exogenous ligands, a-galactosylceramide (a-GalCer) and its analogues [8][9][10][11]. Early reports suggested that iNKT cell protection was associated with the induction of a Th2 response to islet autoantigens [8,[10][11][12].…”

Section: Introductionmentioning

confidence: 77%

“…It has been well established that activation of iNKT cells by repeated aGalCer injections prevents the development of diabetes in NOD mice [8,10,15]. Autoimmunity prevention correlated with the ability of aGalCer to induce iNKT cell anergy and to strongly suppress their IFN-g production while IL-4 production was less inhibited [33].…”

Section: Cd4 à Inkt Cells Containing Inkt17 Cells Enhance the Incidenmentioning

confidence: 95%

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NOD mice contain an elevated frequency of iNKT17 cells that exacerbate diabetes

et al. 2011

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Invariant natural killer T (iNKT) cells are a distinct lineage of innate-like T lymphocytes and converging studies in mouse models have demonstrated the protective role of iNKT cells in the development of type 1 diabetes. Recently, a new subset of iNKT cells, producing high levels of the pro-inflammatory cytokine IL-17, has been identified (iNKT17 cells). Since this cytokine has been implicated in several autoimmune diseases, we have analyzed iNKT17 cell frequency, absolute number and phenotypes in the pancreas and lymphoid organs in non-obese diabetic (NOD) mice. The role of iNKT17 cells in the development of diabetes was investigated using transfer experiments. NOD mice exhibit a higher frequency and absolute number of iNKT17 cells in the lymphoid organs as compared with C57BL/6 mice. iNKT17 cells infiltrate the pancreas of NOD mice where they express IL-17 mRNA. Contrary to the protective role of CD4 1 iNKT cells, the CD4 À iNKT cell population, which contains iNKT17 cells, enhances the incidence of diabetes. Treatment with a blocking anti-IL-17 antibody prevents the exacerbation of the disease. This study reveals that different iNKT cell subsets play distinct roles in the regulation of type 1 diabetes and iNKT17 cells, which are abundant in NOD mice, exacerbate diabetes development.

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Section: Introductionsupporting

confidence: 55%

Section: Introductionmentioning

confidence: 77%

Section: Cd4 à Inkt Cells Containing Inkt17 Cells Enhance the Incidenmentioning

confidence: 95%

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NOD mice contain an elevated frequency of iNKT17 cells that exacerbate diabetes

et al. 2011

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“…iNKT cells are abundant in the liver and rapidly secrete large amounts of immunoregulatory cytokines such as IFN-g and IL-4 after stimulation through their TCR [35][36][37][38][39][40]. Administration of a-GalCer to mice causes rapid release of various cytokines from iNKT cells, which participate in the regulation of various diseases, including tumor rejection and prevention of autoimmune diseases [41][42][43][44][45][46].Although a-GalCer can enhance host resistance against some microbial pathogens [47-55], it remains elusive whether a-GalCer enhances protective immunity against intracellular bacteria.We have recently shown that listeriosis is ameliorated in iNKT-cell-deficient mice [56]. This finding argues against a protective role of iNKT cells in listeriosis.…”

mentioning

confidence: 99%

Retracted: α‐GalCer ameliorates listeriosis by accelerating infiltration of Gr‐1⁺ cells into the liver

Emoto

Yoshizawa

et al. 2010

Eur J Immunol

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a-Galactosylceramide (a-GalCer) activates invariant (i)NKT cells, which in turn stimulate immunocompetent cells. Although activation of iNKT cells appears critical for regulation of immune responses, it remains elusive whether protection against intracellular bacteria can be induced by a-GalCer. Here, we show that a-GalCer treatment ameliorates murine listeriosis, and inhibits inflammation following Listeria monocytogenes infection. Liver infiltration of Gr-1 1 cells and c/d T cells was accelerated by a-GalCer treatment. Gr-1 1 cell and c/d T-cell depletion exacerbated listeriosis in a-GalCer-treated mice, and this effect was more pronounced after depletion of Gr-1 1 cells than that of c/d T cells. Although GM-CSF and IL-17 were secreted by NKT cells after a-GalCer treatment, liver infiltration of Gr-1 1 cells was not prevented by neutralizing mAb. In parallel to the numerical increase of CD11b 1 Gr-1 1 cells in the liver following a-GalCer treatment, CD11b À Gr-1 1 cells were numerically reduced in the bone marrow. In addition, respiratory burst in Gr-1 1 cells was enhanced by a-GalCer treatment. Our results indicate that a-GalCer-induced antibacterial immunity is caused, in part, by accelerated infiltration of Gr-1 1 cells and to a lesser degree of c/d T cells into the liver. We also suggest that the infiltration of Gr-1 1 cells is caused by an accelerated supply from the bone marrow.Key words: a-galactosylceramide . L. monocytogenes . NKT cell Supporting Information available online IntroductionListeria monocytogenes is a Gram-positive facultative intracellular bacterial pathogen, which causes disseminated infection in immunocompromised hosts [1]. Experimental murine listeriosis is instrumental in elucidating host defense mechanisms against intracellular bacteria. Cells of the innate immune system play a pivotal role as a first line of defense against L. monocytogenes [2-5] and among these, Gr-1 1 cells are central for the elimination of this pathogen at early stages of infection [6][7][8]. Numerous cytokines such as GM-CSF, IL-3, IL-6, IL-11, and SCF promote granulopoiesis by themselves and/or in concert with G-CSF [9,10]. G-CSF is indispensable for both steady-state and emergency granulopoiesis [11][12][13][14], and IL-17 regulates G-CSF secretion [9,10,[15][16][17][18]. In addition to Gr-1 1 cells, g/d T cells also participate in early protection against 1328L. monocytogenes infection [19][20][21][22]. The vast majority of L. monocytogenes organisms are trapped in the liver immediately after systemic infection [23] and hence, immunocompetent cells that reside in, and/or migrate into, the liver are critical for infection control.NKT cells represent a unique subset of T lymphocytes, which are characterized by the co-expression of NK cell markers such as NKR-P1B/C (NK1.1; CD161) [24]. In the mouse, the majority of NKT cells express an invariant (i) TCR composed of Va14/Ja18 gene segments, i.e. iNKT cells [24]. In contrast to conventional T cells, which recognize peptide antigens presented by polymorphic MHC ...

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“…NKT cells are a source of IL-4 and were shown to play a beneficial role in T1D [10][11][12][13]. A deficiency of IL-4 production by NKT cell has been reported in murine models of T1D [14,15] and in human T1D patients [16,17].…”

Section: Introductionmentioning

confidence: 99%

Tissue-targeted therapy of autoimmune diabetes using dendritic cells transduced to express IL-4 in NOD mice

Creusot

Yaghoubi²,

Kodama

et al. 2008

Clinical Immunology

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A deficit in IL-4 production has been previously reported in both diabetic human patients and nonobese diabetic (NOD) mice. In addition, re-introducing IL-4 into NOD mice systemically, or as a transgene, led to a beneficial outcome in most studies. Here, we show that prediabetic, 12-wk old female NOD mice have a deficit in IL-4 expression in the pancreatic lymph nodes (PLN) compared to age-matched diabetes-resistant NOD.B10 mice. By bioluminescence imaging, we demonstrated that the PLN was preferentially targeted by bone marrow-derived dendritic cells (DCs) following intravenous (IV) administration. Following IV injection of DCs transduced to express IL-4 (DC/ IL-4) into 12-wk old NOD mice, it was possible to significantly delay or prevent the onset of hyperglycemia. We then focused on the PLN to monitor, by microarray analysis, changes in gene expression induced by DC/IL-4 and observed a rapid normalization of the expression of many genes, that were otherwise under-expressed compared to NOD.B10 PLN. The protective effect of DC/IL-4 required both MHC and IL-4 expression by the DCs. Thus, adoptive cellular therapy, using DCs modified to express IL-4, offers an effective, tissue-targeted cellular therapy to prevent diabetes in NOD mice at an advanced stage of pre-diabetes, and may offer a safe approach to consider for treatment of high risk human pre-diabetic patients.

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Activation of natural killer T cells by α-galactosylceramide treatment prevents the onset and recurrence of autoimmune Type 1 diabetes

Cited by 582 publications

References 33 publications

NOD mice contain an elevated frequency of iNKT17 cells that exacerbate diabetes

NOD mice contain an elevated frequency of iNKT17 cells that exacerbate diabetes

Retracted: α‐GalCer ameliorates listeriosis by accelerating infiltration of Gr‐1⁺ cells into the liver

Tissue-targeted therapy of autoimmune diabetes using dendritic cells transduced to express IL-4 in NOD mice

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Activation of natural killer T cells by α-galactosylceramide treatment prevents the onset and recurrence of autoimmune Type 1 diabetes

Cited by 582 publications

References 33 publications

NOD mice contain an elevated frequency of iNKT17 cells that exacerbate diabetes

NOD mice contain an elevated frequency of iNKT17 cells that exacerbate diabetes

Retracted: α‐GalCer ameliorates listeriosis by accelerating infiltration of Gr‐1+ cells into the liver

Tissue-targeted therapy of autoimmune diabetes using dendritic cells transduced to express IL-4 in NOD mice

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Retracted: α‐GalCer ameliorates listeriosis by accelerating infiltration of Gr‐1⁺ cells into the liver