Development and Function of Invariant Natural Killer T Cells Producing TH2- and TH17-Cytokines

Watarai, Hiroshi; Sekine-Kondo, Etsuko; Shigeura, Tomokuni; Motomura, Yasutaka; Yasuda, Tomohiko; Satoh, Rumi; Yoshida, Hisahiro; Kubo, Masato; Kawamoto, Hiroshi; Koseki, Haruhiko; Taniguchi, Masaru

doi:10.1371/journal.pbio.1001255

Cited by 182 publications

(236 citation statements)

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“…[12][13][14] More recently, several investigators have proposed three iNKT sublineages based on thymic development and distinct functions. [14][15][16][17][18] These sublineages include NKT1 cells, which have high expression of the T-box transcription factor T-bet (Th1-like iNKT cells) and secrete large amounts of IFN-c upon stimulation; NKT2 cells highly express GATA-binding protein 3 (GATA-3) (Th2-like iNKT cells) and produce IL-4 upon stimulation, whereas NKT-17 cells (Th17-like iNKT cells) express high levels of retinoic acid receptor-related orphan receptor-ct (RORct) and produce IL-17 under activated conditions. 17 The above description raises the possibility that the function of specific iNKT cell sublineages may be determined by transcriptional programs.…”

Section: Introductionmentioning

confidence: 99%

“…[14][15][16][17][18] These sublineages include NKT1 cells, which have high expression of the T-box transcription factor T-bet (Th1-like iNKT cells) and secrete large amounts of IFN-c upon stimulation; NKT2 cells highly express GATA-binding protein 3 (GATA-3) (Th2-like iNKT cells) and produce IL-4 upon stimulation, whereas NKT-17 cells (Th17-like iNKT cells) express high levels of retinoic acid receptor-related orphan receptor-ct (RORct) and produce IL-17 under activated conditions. 17 The above description raises the possibility that the function of specific iNKT cell sublineages may be determined by transcriptional programs. 19 During iNKT cell development, several transcription factors are involved in regulating phenotype and function, including a BTB-ZF promyelocyticzinc finger transcription regulator, which is specifically expressed in iNKT cells.…”

Section: Introductionmentioning

confidence: 99%

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Runt-related transcription factor 3 is involved in the altered phenotype and function in ThPok-deficient invariant natural killer T cells

et al. 2014

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The interplay between the CD4-lineage transcription factor ThPok and the CD8-lineage transcription factor, runt-related transcription factor 3 (Runx3), in T-cell development has been extensively documented. However, little is known about the roles of these transcription factors in invariant natural killer T (iNKT) cell development. CD1d-restricted iNKT cells are committed to the CD4 1 CD8 2 and CD4 2 CD8 2 sublineages, which respond to antigen stimulation with rapid and potent release of T helper (Th) 1 and Th2 cytokines. However, previous reports have demonstrated a new population of CD8 1 NKT cells in ThPok-deficient mice. In the current study, we sought to determine whether Runx3 was involved in the re-expression of CD8 and function of iNKT cells in the absence of ThPok. We used mice lacking Runx3, ThPok or both and verified that Runx3 was partially responsible for the appearance of CD8 1 iNKT cells in ThPok knockout mice. Additionally, Runx3 participated in the immune response mediated by iNKT cells in a model of a-galactosylceramide-induced acute hepatitis. These results indicate that Runx3 is crucial for the phenotypic and functional changes observed in ThPok-deficient iNKT cells. and the canonical T-cell receptor a (TCRa) chain (Va14-Ja18 in mice and V24-J18 in humans) coupled to specific Vb chains (Vb8, Vb7 and Vb2 in mice and Vb11 in humans). These receptors are responsible for the interaction of NKT cells with CD1d molecules expressed on CD4 1 CD8 1 double-positive (DP) thymocytes. 1 NKT cells are classified into type I (defined as invariant (iNKT) or classical NKT cells) and type II based on the antigens recognized by each and their TCR repertoires. 2 Our study focused on type I NKT cells (hereafter referred to as iNKT cells). iNKT cells recognize the glycosphingolipid antigen a-galactosylceramide (a-GalCer) and a-GalCer loading with the tetrameric form of CD1d is often used to define the iNKT cell subset because of the high affinity of CD1d for the iNKT cell TCR. 3 Although iNKT cells originate from CD4 1 CD8 1 (DP) thymocytes 4 and are selected by MHC class

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Runt-related transcription factor 3 is involved in the altered phenotype and function in ThPok-deficient invariant natural killer T cells

et al. 2014

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“…Three subsets of iNKT cells, referred to as iNKT1, iNKT2, and iNKT17, have recently been identified according to differential expression of PLZF, T-bet, IL-17RB, and Rorγt, and distinct cytokine profiles (10,12). Analysis of spleen and lymph node cells revealed that the number of all three iNKT subsets was reduced in Fnip1 −/− mice (Fig.…”

Section: Resultsmentioning

confidence: 99%

Metabolic regulator Fnip1 is crucial for iNKT lymphocyte development

Park

Tsang

Iritani

et al. 2014

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

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Folliculin-interacting protein 1 (Fnip1) is an adaptor protein that physically interacts with AMPK, an energy-sensing kinase that stimulates mitochondrial biogenesis and autophagy in response to low ATP, while turning off energy consumption mediated by mammalian target of rapamycin. Previous studies with Fnip1-null mice revealed that Fnip1 is essential for pre-B-cell development. Here we report a critical role of Fnip1 in invariant natural killer T (iNKT) cell development. Thymic iNKT development in Fnip1 −/− mice was arrested at stage 2 (NK1.1 − CD44 + ) but development of CD4, CD8, γδ T-cell, and NK cell lineages proceeded normally. Enforced expression of a Vα14Jα18 iNKT TCR transgene or loss of the proapoptotic protein Bim did not rescue iNKT cell maturation in Fnip1 −/− mice. Whereas most known essential transcription factors for iNKT cell development were represented normally, Fnip1 −/− iNKT cells failed to down-regulate Promyelocytic leukemia zinc finger compared with their WT counterparts. Moreover, Fnip1 −/− iNKT cells contained hyperactive mTOR and reduced mitochondrial number despite lower ATP levels, resulting in increased sensitivity to apoptosis. These results indicate that Fnip1 is vital for iNKT cell development by maintaining metabolic homeostasis in response to metabolic stress. metabolism | thymus | Birt-Hogg-Dubé syndrome

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“…Similar to NK cells [52], slp-76 ace/ace iNKT cells more frequently expressed NK-cell receptors (especially NK1.1, NKG2D, and Ly49G2) and CD122 than their B6 counterparts (Supporting Information Table 1). In contrast, IL-17RB, which is predominantly expressed on NKT2 and NKT17 cells [18], was selectively reduced (Supporting Information ADAP −/− mice exhibited no significant differences in the expression of any of these markers compared to control mice (data not shown). Although based on these observations the slp-76 ace/ace mutation was expected to favor a Th1-polarization, iNKT cells from slp-76 ace/ace mice released less IL-4, and IFN-γ upon stimulation with α-GalCer compared to WT cells, i.e.…”

mentioning

confidence: 99%

“…Th2-or Th-17-polarized iNKT cells maintain their PLZF-expression at high or intermediate levels, respectively, and are primarily recovered from the lungs and peripheral lymph nodes [8,12,15]. Both subsets frequently express IL-17RB [18] and NP-1 which characterizes iNKT cells that recently emigrated from the thymus [19]. However, the role of NP-1 in iNKT cell biology has remained undefined.…”

mentioning

confidence: 99%

A mutation within the SH2 domain of slp‐76 regulates the tissue distribution and cytokine production of iNKT cells in mice

et al. 2016

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TCR ligation is critical for the selection, activation, and integrin expression of T lymphocytes. Here, we explored the role of the TCR adaptor protein slp-76 on iNKT-cell biology. Compared to B6 controls, slp-76 ace/ace mice carrying a missense mutation (Thr428Ile) within the SH2-domain of slp-76 showed an increase in iNKT cells in the thymus and lymph nodes, but a decrease in iNKT cells in spleens and livers, along with reduced ADAP expression and cytokine response. A comparable reduction in iNKT cells was observed in the livers and spleens of ADAP-deficient mice. Like ADAP −/− iNKT cells, slp-76 ace/ace iNKT cells were characterized by enhanced CD11b expression, correlating with an impaired induction of the TCR immediate-early gene Nur77 and a decreased adhesion to ICAM-1. Furthermore, CD11b-intrinsic effects inhibited cytokine release, concanavalin A-mediated inflammation, and iNKT-cell accumulation in the liver. Unlike B6 and ADAP −/− mice, the expression of the transcription factors Id3 and PLZF was reduced, whereas NP-1-expression was enhanced in slp-76 ace/ace mice. Blockade of NP-1 decreased the recovery of iNKT cells from peripheral lymph nodes, identifying NP-1 as an iNKT-cell-specific adhesion factor. Thus, slp-76 contributes to the regulation of the tissue distribution, PLZF, and cytokine expression of iNKT cells via ADAP-dependent and -independent mechanisms.Keywords: ADAP r Cytokine r iNKT cell r Integrin r slp-76Additional supporting information may be found in the online version of this article at the publisher's web-site Eur. J. Immunol. 2016Immunol. . 46: 2121Immunol. -2136 Introduction iNKT cells express a panoply of NK-cell receptors [1] and a canonical TCR through which they recognize (glyco-)lipid antigens [2]. iNKT cells activate similar signaling cascades after TCR ligation like other T lymphocytes [3], but utilize unique transcription factors for their development such as the promyelocytic leukemia zinc finger (PLZF) [4][5][6]. According to two different developmental models PLZF characterizes distinct maturation stages and polarized subsets. The sequential lineage model suggests a gradual decrease of PLZFexpression following selection of iNKT cells which show a Th2-dominated cytokine profile during earlier and a Th1-dominated cytokine profile during later stages of intrathymic maturation [1,7]. The second model describes lineage diversification and simultaneous differentiation into Th1-, Th2-, or Th17-polarized subsets that are defined by the level of PLZF-expression [8]. Although many iNKT cells release both Th1 and Th2 cytokines on a single cell level [9], the production of IL-17 and IFN-γ is mutually exclusive within NK1.1 − cells [10][11][12]. Several transcription factors, such as Egr2, T-bet, ThPOK, Id2, Id3, and the Tec kinases Itk and Rlk have been implicated in the differentiation of iNKT cell subsets [6,8,[13][14][15][16][17] which home to distinct tissues. Specifically, liver and spleen constitute the main source for the Th1-polarized sublineage which is PLZF low . Th2-or ...

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Development and Function of Invariant Natural Killer T Cells Producing TH2- and TH17-Cytokines

Abstract: Four distinct subsets of invariant natural killer T (NKT) cells are shown to differentiate in the thymus, then migrate to peripheral tissues where they retain their phenotypic and functional characteristics.

Cited by 182 publications

References 59 publications

Runt-related transcription factor 3 is involved in the altered phenotype and function in ThPok-deficient invariant natural killer T cells

Runt-related transcription factor 3 is involved in the altered phenotype and function in ThPok-deficient invariant natural killer T cells

Metabolic regulator Fnip1 is crucial for iNKT lymphocyte development

A mutation within the SH2 domain of slp‐76 regulates the tissue distribution and cytokine production of iNKT cells in mice

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