Prevention of Diabetes in Nonobese Diabetic Mice Mediated by CD1d-Restricted Nonclassical NKT Cells

Duarte, Nádia; Stenström, Martin; Campino, Susana; Bergman, Marie‐Louise; Lundholm, Marie; Holmberg, Dan; Cardell, Susanna

doi:10.4049/jimmunol.173.5.3112

Cited by 94 publications

(83 citation statements)

References 41 publications

(61 reference statements)

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“…Consistently, only a low expression of CD69 is found on most of the tetramer + cells (Fig. 1A), similar to other Vα3.2/Vβ9 + type II NKT cells (27,28). It is remarkable that in the absence of any external immunization with the antigen, spectratyping (Fig.…”

Section: Discussionsupporting

confidence: 80%

See 1 more Smart Citation

Oligoclonality and innate-like features in the TCR repertoire of type II NKT cells reactive to a β-linked self-glycolipid

Arrenberg

Halder

Dai

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

108

144

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TCR-mediated recognition of β-linked self-glycolipids bound to CD1d is poorly understood. Here, we have characterized the TCR repertoire of a CD1d-restricted type II NKT cell subset reactive to sulfatide involved in the regulation of autoimmunity and antitumor immunity. The sulfatide/CD1d-tetramer + cells isolated from naïve mice show an oligoclonal TCR repertoire with predominant usage of the Vα3/Vα1-Jα7/Jα9 and Vβ8.1/Vβ3.1-Jβ2.7 gene segments. The CDR3 regions of both the α- and β-chains are encoded by either germline or nongermline gene segments of limited lengths containing several conserved residues. Presence of dominant clonotypes with limited TCR gene usage for both TCR α- and β-chains in type II NKT cells reflects specific antigen recognition not found in the type I NKT cells but similar to the MHC-restricted T cells. Although potential CD1d-binding tyrosine residues in the CDR2β region are conserved between most type I and type II NKT TCRs, CDR 1α and 3α regions differ significantly between the two subsets. Collectively, the TCR repertoire of sulfatide-reactive type II NKT cells exhibits features of both antigen-specific conventional T cells and innate-like cells, and these findings provide important clues to the recognition of β-linked glycolipids by CD1d-restricted T cells in general.

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Section: Discussionsupporting

confidence: 80%

“…Consistent with this idea, a number of CD1d-reactive T cell hybrids isolated from MHC class II-deficient mice (15,16,28) are Vα3 + , Vα8 + , and Vα4 + and do not show any reactivity to sulfatide (17,18). Accordingly, none of them expressed the TCR Vα-Jα and Vβ-Jβ gene segments predominantly used by sulfatide/CD1d-tetramer + cells.…”

Section: Discussionmentioning

confidence: 69%

Oligoclonality and innate-like features in the TCR repertoire of type II NKT cells reactive to a β-linked self-glycolipid

Arrenberg

Halder

Dai

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

108

144

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“…In human bone marrow such noninvariant type II NKT cells were found to be skewed toward Th2 cytokines and to suppress an alloantigenspecific proliferative response (mixed lymphocyte response) (111). A TCR V␣3.2 ϩ V␤9 ϩ (type II) NKT cell was found able to suppress autoimmune diabetes in NOD mice (112). Also, type II NKT cells reactive with sulfatide, a lipid derived from myelin sheaths, were found to protect against EAE, a mouse model of multiple sclerosis (113).…”

Section: Type II Nkt Cells In Tumor Immunity and Immune Regulationmentioning

confidence: 99%

NKT Cells in Tumor Immunity: Opposing Subsets Define a New Immunoregulatory Axis

Berzofsky

Terabe

2008

The Journal of Immunology

108

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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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Prevention of Diabetes in Nonobese Diabetic Mice Mediated by CD1d-Restricted Nonclassical NKT Cells

Cited by 94 publications

References 41 publications

Oligoclonality and innate-like features in the TCR repertoire of type II NKT cells reactive to a β-linked self-glycolipid

Oligoclonality and innate-like features in the TCR repertoire of type II NKT cells reactive to a β-linked self-glycolipid

NKT Cells in Tumor Immunity: Opposing Subsets Define a New Immunoregulatory Axis

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

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