IL-17–producing invariant NKT cells in lymphoid organs are recent thymic emigrants identified by neuropilin-1 expression

Milpied, Pierre; Massot, Bérangère; Renand, Amédée; Diem, Séverine; Herbelin, André; Leite‐de‐Moraes, Maria; Rubio, Marie‐Thérèse; Hermine, Olivier

doi:10.1182/blood-2011-01-329268

Cited by 62 publications

(61 citation statements)

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“…Neuropilin-1 (Nrp-1) was detected as described elsewhere (24). For intracellular cytokine detection, cells were incubated for 2 h 30 min with 50 ng/ml 4-a-phorbol 12-mystrate 13-acetate, 500 ng/ml ionomycin, and 10 mg/ml brefeldin A (Sigma).…”

Section: Flow Cytometry and Cell Sortingmentioning

confidence: 99%

“…Effector CD4 T cells that specialize in IL-17 secretion, termed Th17 cells, differentiate in the periphery after activation in presence of TGF-b, IL-6, and IL1b produced mainly by innate cells, and rely on IL-23 and IL-21 for maturation and expansion after Th17 commitment (20)(21)(22). In contrast, IL-17-secreting iNKT cells are believed to belong to a distinct lineage that develops in the thymus, are more immature than iNKT cells that produce IFN-g and IL-4, and constitute a subset of recent thymic iNKT cell emigrants (23,24). However, the possibility that mature, uncommitted iNKT cells can respond to activation under the influence of particular cytokines by secreting IL-17 was never addressed.…”

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confidence: 99%

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Induced IL-17–Producing Invariant NKT Cells Require Activation in Presence of TGF-β and IL-1β

Monteiro

Almeida

Agua-Doce

et al. 2013

The Journal of Immunology

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IL-17 production by innate-like lymphocytes, including γδ and invariant NKT (iNKT) cells, have been ascribed to specific lineages that are endowed with this functional specialization during thymic differentiation. IL-17–producing iNKT cells have been described as a CD4−NK1.1− lineage in mice and CD161+ in humans. We found that, in mice, noncommitted iNKT cells can be induced to produce IL-17 when activated in presence of TGF-β and IL-1β. This peripheral induction of IL-17 expression could be observed in any subset irrespectively of CD4 and NK1.1 expression, the process leading to loss of NK1.1 expression and partial CD4 downmodulation. Furthermore, induced IL-17–producing iNKT cells were sufficient to drive neutrophilic airways inflammation upon intratracheal adoptive cell transfer into congenic mice. Taken together, our data show that similarly to regulatory T cells, which have a natural and peripherally induced subset, IL-17 production by iNKT cells can also be imprinted in natural iNKT17 cells or peripherally induced.

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Section: Flow Cytometry and Cell Sortingmentioning

confidence: 99%

mentioning

confidence: 99%

Induced IL-17–Producing Invariant NKT Cells Require Activation in Presence of TGF-β and IL-1β

Monteiro

Almeida

Agua-Doce

et al. 2013

The Journal of Immunology

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“…To our knowledge, CX3CR1 expression within developing iNKT thymocytes has not been previously reported and, apart from one study that defines neuropilin-1 as a marker for emigrating IL-17-producing iNKT cells (9), this is the first study to identify a marker for emigration expressed within the NKT1, NKT2, and NKT17 sublineages. In this context, our primary analysis of differentially expressed mRNAs within emigrating iNKT lymphocytes corroborates the finding that mRNA for neuropilin-1 is upregulated within iNKT RTEs (Supplemental Table II); however, the fold-change observed for neuropilin-1 was 610-fold less than that observed for Cx3cr1 mRNA within iNKT RTEs (Supplemental Table II).…”

Section: Discussionmentioning

confidence: 97%

The Thymic Microenvironment Differentially Regulates Development and Trafficking of Invariant NKT Cell Sublineages

Drennan

Govindarajan

Wilde

et al. 2014

The Journal of Immunology

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The regulatory role of the thymic microenvironment during trafficking and differentiation of the invariant NKT (iNKT) cell lineage remains poorly understood. In this study, we show that fractalkine receptor expression marks emigrating subpopulations of the NKT1, NKT2, and NKT17 sublineages in the thymus and peripheral organs of naive mice. Moreover, NKT1 sublineage cells can be subdivided into two subsets, namely NKT1a and NKT1b, which exhibit distinct developmental and tissue-specific distribution profiles. More specifically, development and trafficking of the NKT1a subset are selectively dependent upon lymphotoxin (LT)α1β2-LTβ receptor–dependent differentiation of thymic stroma, whereas the NKT1b, NKT2, and NKT17 sublineages are not. Furthermore, we identify a potential cellular source for LTα1β2 during thymic organogenesis, marked by expression of IL-7Rα, which promotes differentiation of the NKT1a subset in a noncell-autonomous manner. Collectively, we propose a mechanism by which thymic differentiation and retention of the NKT1 sublineage are developmentally coupled to LTα1β2-LTβ receptor–dependent thymic organogenesis.

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“…While there was no difference in the expression of CXCR6, CXCR3, CCL21, LFA-1, and CCR7, significantly more iNKT cells were NP-1 + in the peripheral lymph nodes of slp-76 ace/ace compared to B6 mice (Fig. 5E, F) suggesting an accumulation of recent iNKT cell thymic emigrants at this organ site [19]. As no differences in the expression of NP-1 were observed between ADAP −/− and control mice (data not shown), these data suggested that slp-76 is sufficient for the regulation of NP-1 on iNKT cells.…”

Section: Slp-76 Requires Adap For the Regulation Of Lfa-1-and Cd11b-mentioning

confidence: 95%

“…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.…”

Section: Introductionmentioning

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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IL-17–producing invariant NKT cells in lymphoid organs are recent thymic emigrants identified by neuropilin-1 expression

Cited by 62 publications

References 50 publications

Induced IL-17–Producing Invariant NKT Cells Require Activation in Presence of TGF-β and IL-1β

Induced IL-17–Producing Invariant NKT Cells Require Activation in Presence of TGF-β and IL-1β

The Thymic Microenvironment Differentially Regulates Development and Trafficking of Invariant NKT Cell Sublineages

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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