Expansion and long-range differentiation of the NKT cell lineage in mice expressing CD1d exclusively on cortical thymocytes

Wei, Datsen G.; Lee, Hyunji; Park, Seho; Beaudoin, Lucie; Teyton, Luc; Lehuen, Agnès; Bendelac, Albert

doi:10.1084/jem.20050413

Cited by 141 publications

(146 citation statements)

References 44 publications

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“…As a result, a hyperreactive response to ␣GalCer presented by DCs might be expected if iNKT cells had never been exposed to DCs. This type of hyperreactivity was reported recently in pLck-CD1d mice that express CD1d only in the thymus (56). NKT cells in these mice barely responded to free ␣GalCer, but produced extremely high levels of cytokines in response to ␣GalCer loaded on DCs in vitro and in vivo (56).…”

Section: Discussionsupporting

confidence: 67%

“…This type of hyperreactivity was reported recently in pLck-CD1d mice that express CD1d only in the thymus (56). NKT cells in these mice barely responded to free ␣GalCer, but produced extremely high levels of cytokines in response to ␣GalCer loaded on DCs in vitro and in vivo (56). It is unclear whether self peptide Ags displayed by DCs are also uniquely fueling the responsiveness of conventional T cells to foreign Ags.…”

Section: Discussionmentioning

confidence: 62%

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Efficient Activation of Vα14 Invariant NKT Cells by Foreign Lipid Antigen Is Associated with Concurrent Dendritic Cell-Specific Self Recognition

Ueno

Cho

et al. 2007

The Journal of Immunology

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A burst release of cytokines by Vα14 invariant NKT (iNKT) cells upon their TCR engagement critically regulates innate and adaptive immune responses. However, it remains unclear in vivo why iNKT cells respond efficiently to microbial or intracellular lipid Ags that are at low levels or that possess suboptimal antigenicity. We found that dendritic cells (DCs) potentiated iNKT cells to respond to a minimal amount of ligand α-galactosylceramide (αGalCer) through CD1d-dependent autoreactive responses that require endosomal processing and CD1d trafficking. The ability of potentiation of NKT cells was DC specific and did not depend on costimulatory signals and IL-12 production by DCs. However, DCs that failed to synthesize a major endogenous lipid Ag isoglobotrihexosylceramide were unable to potentiate NKT cells for efficient activation. Further analysis showed that differences in the level and pattern of endogenous lipid Ag presentation differentiate DCs and B cells for effective potentiation and subsequent activation of iNKT cells in the presence of an exogenous Ag. Thus, CD1d-dependent potentiation by DCs may be crucial for iNKT cell-mediated immunity against infectious agents.

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Section: Discussionsupporting

confidence: 67%

Section: Discussionmentioning

confidence: 62%

Efficient Activation of Vα14 Invariant NKT Cells by Foreign Lipid Antigen Is Associated with Concurrent Dendritic Cell-Specific Self Recognition

Ueno

Cho

et al. 2007

The Journal of Immunology

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“…The great majority of murine NKT cells express an invariant TCR V␣ and J␣ combination (V␣14-J␣18) that is preferentially paired with a restricted TCR ␤-chain (mostly V␤8.2 or V␤7), and recognize lipid Ags in the context of CD1d (3,4). These cells develop in the thymus from CD4 ϩ 8 ϩ (double-positive (DP)) 3 thymocyte progenitors, and are positively selected by interactions with other CD1d ϩ / signaling lymphocytic activating molecule (SLAM) ϩ DP cortical thymocytes (5,6). Upon positive selection, NKT cells acquire markers characteristic of memory T cells, such as CD44 (7).…”

mentioning

confidence: 99%

The Tec Kinases Itk and Rlk Regulate NKT Cell Maturation, Cytokine Production, and Survival

Felices

Berg

2008

The Journal of Immunology

105

125

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The Tec kinases Itk and Rlk are required for efficient positive selection of conventional CD4+ and CD8+ T cells in the thymus. In contrast, recent studies have shown that these Tec kinases are dispensable for the development of CD8+ T cells with characteristics of innate T cells. These findings raise questions about the potential role of Itk and Rlk in NKT cell development, because NKT cells represent a subset of innate T cells. To address this issue, we examined invariant NKT cells in Itk−/− and Itk/Rlk−/− mice. We find, as has been reported previously, that Itk−/− mice have reduced numbers of NKT cells with a predominantly immature phenotype. We further show that this defect is greatly exacerbated in the absence of both Itk and Rlk, leading to a 7-fold reduction in invariant NKT cell numbers in the thymus of Itk/Rlk−/− mice and a more severe block in NKT cell maturation. Splenic Itk−/− and Itk/Rlk−/− NKT cells are also functionally defective, because they produce little to no cytokine following in vivo activation. Tec kinase-deficient NKT cells also show enhanced cell death in the spleen. These defects correlate with greatly diminished expression of CD122, the IL-2R/IL-15R β-chain, and impaired expression of the T-box transcription factor, T-bet. These data indicate that the Tec kinases Itk and Rlk provide important signals for terminal maturation, efficient cytokine production, and peripheral survival of NKT cells.

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“…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 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].…”

mentioning

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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Expansion and long-range differentiation of the NKT cell lineage in mice expressing CD1d exclusively on cortical thymocytes

Cited by 141 publications

References 44 publications

Efficient Activation of Vα14 Invariant NKT Cells by Foreign Lipid Antigen Is Associated with Concurrent Dendritic Cell-Specific Self Recognition

Efficient Activation of Vα14 Invariant NKT Cells by Foreign Lipid Antigen Is Associated with Concurrent Dendritic Cell-Specific Self Recognition

The Tec Kinases Itk and Rlk Regulate NKT Cell Maturation, Cytokine Production, and Survival

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

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