CD1d-expressing Dendritic Cells but Not Thymic Epithelial Cells Can Mediate Negative Selection of NKT Cells

Chun, Taehoon; Page, Michael; Gapin, Laurent; Matsuda, Jennifer L.; Xu, Hui; Nguyen, Hanh; Kang, Hyung Sik; Stanic, Aleksandar K.; Joyce, Sebastian; Koltun, Walter A.; Chorney, Michael J.; Kronenberg, Mitchell; Wang, Chyung Ru

doi:10.1084/jem.20021366

Cited by 127 publications

(161 citation statements)

References 69 publications

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“…However, the CD1d deficiency per se does not appear to directly cause the expansion of this cell population, as the numbers of TCR § g + B220 + cells were comparable in the peripheral lymphoid tissues of normal B6 and CD1d -/-B6 mice (our unpublished data). Furthermore, whereas up-regulation of CD1d on dendritic cells has been found to lead to excessive negative selection of NKT cells [42], it appears to have no effect on the conventional CD8 and CD4 compartments or on TCR § g + B220 + cells [43]. The levels of CD1d expression on dendritic cells and thymocytes in MRL-lpr mice are also comparable to those of B6 mice (our unpublished data).…”

Section: Discussionmentioning

confidence: 54%

CD1d deficiency exacerbates inflammatory dermatitis in MRL‐lpr/lpr mice

et al. 2004

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Mechanisms responsible for the development of autoimmune skin disease in humans and animal models with lupus remain poorly understood. In this study, we have investigated the role of CD1d, an antigen-presenting molecule known to activate natural killer T cells, in the development of inflammatory dermatitis in lupus-susceptible MRL-lpr/lpr mice. In particular, we have established MRL-lpr/lpr mice carrying a germ-line deletion of the CD1d genes. We demonstrate that CD1d-deficient MRL-lpr/lpr mice, as compared with wild-type littermates, have more frequent and more severe skin disease, with increased local infiltration with mast cells, lymphocytes and dendritic cells, including Langerhans cells. CD1d-deficient MRL-lpr/ lpr mice had increased prevalence of CD4 + T cells in the spleen and liver and of TCR § g + B220 + cells in lymph nodes. Furthermore, CD1d deficiency was associated with decreased T cell production of type 2 cytokines and increased or unchanged type 1 cytokines. These findings indicate a regulatory role of CD1d in inflammatory dermatitis. Understanding the mechanisms by which CD1d deficiency results in splenic T cell expansion and cytokine alterations, with increased dermal infiltration of dendritic cells and lymphocytes in MRL-lpr/lpr mice, will have implications for the pathogenesis of inflammatory skin diseases.

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Section: Discussionmentioning

confidence: 54%

CD1d deficiency exacerbates inflammatory dermatitis in MRL‐lpr/lpr mice

et al. 2004

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Section: Introductionmentioning

confidence: 99%

“…Unlike conventional MHC-dependent T cells, Va14i NKT cells are not positively selected by thymic epithelial cells but rather by hematopoietic cells [2,[15][16][17][18], in particular by CD1d-expressing DP cortical thymocytes [19,20], which alone are sufficient for positive selection of Va14i NKT cells [21,22]. Furthermore, Va14i NKT cells can be negatively selected by very strong activation signals provided by thymic DC [22,23] or DP cortical thymocytes [22].The key event deciding for selection of Va14i NKT cells is the appropriate presentation of endogenous thymic lipid antigen(s) by CD1d. Many steps are involved in this process, including proper conformation of the CD1d molecule, correct intracellular trafficking of lipids and CD1d, generation of lipid antigen(s), and loading of the lipid antigen(s) onto CD1d in late endosomes/lysosomes [24][25][26][27].…”

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confidence: 99%

Differential alteration of lipid antigen presentation to NKT cells due to imbalances in lipid metabolism

et al. 2007

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Deficiencies in enzymes of the lysosomal glycosphingolipid degradation pathway or in lysosomal lipid transfer proteins cause an imbalance in lipid metabolism and induce accumulation of certain lipids. A possible impact of such an imbalance on the presentation of lipid antigens to lipid-reactive T cells has only been hypothesized but not extensively studied so far. Here we demonstrate that presentation of lipid antigens to, and development of, lipid-reactive CD1d-restricted NKT cells, are impaired in mice deficient in the lysosomal enzyme b-galactosidase (bGal) or the lysosomal lipid transfer protein Niemann-Pick C (NPC) 2. Importantly, the residual populations of NKT cells selected in bGal -/-and NPC2 -/-mice showed differential TCR and CD4 repertoire characteristics, suggesting that differential selecting CD1d:lipid antigen complexes are formed. Furthermore, we provide direct evidence that accumulation of lipids impairs lipid antigen presentation in both cases. However, the mechanisms by which imbalanced lipid metabolism affected lipid antigen presentation were different. Based on these results, the impact of lipid accumulation should be generally considered in the interpretation of immunological deficiencies found in mice suffering from lipid metabolic disorders.Supporting information for this article is available at http://www.wiley-vch.de/contents/jc_2040/2007/37160_s.pdf IntroductionDefects in lysosomal lipid trafficking or degradation result in a severe imbalance of lipid metabolism. Little is known about the consequences of such an imbalance on the presentation of lipid antigens to lipid-reactive T cells, e.g., the important immunoregulatory invariant (i) NKT cell subset (Va14i and Va24i NKT cells in mice and humans, respectively), which recognizes glycolipid antigens presented by the MHC class I-like molecule Abbreviations: a-GalCer: a-galactosylceramide (KRN7000) Á a/bGal: a/b-galactosidase Á DN: CD4 -CD8 -double negative Á DP: CD4 + CD8 + double positive Á Hex: hexosaminidase Á HSA: heat-stable Ag Á i: invariant Á iGb3: isoglobotrihexosylceramide Á NB-DNJ: N-butyldeoxynojirimycin Á NPC: NiemannPick C Eur. J. Immunol. 2007Immunol. . 37: 1431Immunol. -1441 CD1d. In mice, the TCR of Va14i NKT cells is composed of an invariant Va14-Ja18 chain, paired preferentially with a restricted b chain, mostly containing Vb8.2 or Vb7 (the human equivalents are Va24-Ja18 and Vb11) [1][2][3][4]. Va14i NKT cells are implicated in the regulation of antitumor immunity, antimicrobial responses, and the balance between tolerance and autoimmunity [5,6]. Va14i NKT cells, which can be either CD4 + or CD4 -CD8 -double negative (DN), are a thymus-dependent population derived from CD4 + CD8 + double-positive (DP) thymocytes [7][8][9][10][11]. Different maturation stages of developing thymic Va14i NKT cells have been described, characterized by the sequential acquisition of CD44 and NK1.1 in C57BL/6 mice [12][13][14]. Unlike conventional MHC-dependent T cells, Va14i NKT cells are not positively selected by thymic epithelial cell...

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“…Furthermore, over-expression of CD1d resulted in a thymic deletion of high-affinity CD1d-restricted NKT cells in transgenic mice, as well drastically reduced frequency of NKT cells in FTOC, suggesting negative selection of NKT cells may be influenced by ligand expressing cells in the thymus through altering ligand density. Particularly, CD1d expressing thymic stromal cells, mainly DCs, rather than DP thymocytes mediated negative selection of NKT cells, and CD4 + NKT cells formed the majority of these deleted NKT cells [22] . Rarity in humans, even deficiency in mice, of CD8 + SP NKT cells suggests a possible mechanism of CD8-mediated negative selection during CD8 + SP NKT cell development.…”

Section: Basic Pathway Of Nkt Cell Developmentmentioning

confidence: 99%

“…A dose-and time-dependent deletion of NKT cells is induced by the injection of high dose of the glycolipid agonist α-GalCer to fetal thymic organ culture (FTOC) or persistent injection to young adult mice [22] . Similarly, the intrathymic NKT cell development is specifically blocked by the TCR-mediated selective signals, which strongly suggests NKT cells are subject to negative selection if they are highly reactive to self-glycolipid ligands during their development [23] .…”

Section: Basic Pathway Of Nkt Cell Developmentmentioning

confidence: 99%

Type I natural killer T cells: naturally born for fighting

et al. 2010

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Type І natural killer T cells (NKT cells), a subset of CD1d-restricted T cells with invariant Vαβ TCR, are characterized by prompt production of large amounts of Th1 and/or Th2 cytokines upon primary stimulation through the TCR complex. The rapid release of cytokines implies that type І NKT cells may play a critical role in modulating the upcoming immune responses, such as anti-tumor response, protection against infection, and autoimmunity. As a bridge between innate and adaptive immunity, type І NKT cells differentiate and mature upon stimulations to achieve and maintain a homeostasis. Orchestrating with other arms of adaptive immunity, type І NKT cells show strong cytotoxic effects in response to various tumors in a direct and/or indirect manner(s). This review will focus primarily on type І NKT cell development, homeostasis, and effector functions, especially in anti-tumor immunity, and followed by their potential applications in treatment of cancers.

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CD1d-expressing Dendritic Cells but Not Thymic Epithelial Cells Can Mediate Negative Selection of NKT Cells

Cited by 127 publications

References 69 publications

CD1d deficiency exacerbates inflammatory dermatitis in MRL‐lpr/lpr mice

CD1d deficiency exacerbates inflammatory dermatitis in MRL‐lpr/lpr mice

Differential alteration of lipid antigen presentation to NKT cells due to imbalances in lipid metabolism

Type I natural killer T cells: naturally born for fighting

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