Cutting Edge: The Chemokine Receptor CXCR3 Retains Invariant NK T Cells in the Thymus

Drennan, Michael; Franki, Ann Sophie; Dewint, Pieter; Beneden, Katrien Van; Seeuws, Sylvie; Pavert, Serge A. van de; Reilly, Emma; Verbruggen, Gust; Lane, Thomas E.; Mebius, Reina E.; Deforce, Dieter; Elewaut, Dirk

doi:10.4049/jimmunol.0901213

Cited by 37 publications

(53 citation statements)

References 17 publications

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“…However, they did not mention which background and Abs were used for the determination of intrahepatic NK + cells in CXCR3-deficient mice. Interestingly, a further study demonstrated that the chemokine receptor CXCR3 is necessary to retain NKT cells in the thymus (25). Hence, CXCR3 2/2 mice harbored an increased frequency of NKT cells in the periphery, in line with our results.…”

Section: Discussionsupporting

confidence: 81%

CXCR3 Deficiency Exacerbates Liver Disease and Abrogates Tolerance in a Mouse Model of Immune-Mediated Hepatitis

Erhardt

Wegscheid

Claass

et al. 2011

The Journal of Immunology

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The chemokine receptor CXCR3 is preferentially expressed by Th1 cells and critically involved in their recruitment to inflamed tissue. In a mouse model of immune-mediated liver injury inducible by Con A, we investigated the role of CXCR3 in acute IFN-γ–mediated hepatitis as well as in tolerance induction, which has been shown to depend on IL-10–producing CD4+CD25+Foxp3+ regulatory T cells (Tregs). Induction of Con A hepatitis resulted in increased intrahepatic expression of the CXCR3 ligands CXCL9, CXCL10, and CXCL11. CXCR3−/− mice developed a more severe liver injury with higher plasma transaminase activities and a more pronounced Th1/Th17 response compared with wild-type (wt) animals upon Con A injection. Moreover, CXCR3−/− mice did not establish tolerance upon Con A restimulation, although Tregs from CXCR3−/− mice were still suppressive in an in vitro suppression assay. Instead, Tregs failed to accumulate in livers of CXCR3−/− mice upon Con A restimulation in contrast to those from wt animals. Con A-tolerant wt mice harbored significantly increased numbers of intrahepatic CXCR3+T-bet+ Tregs that produced IL-10 compared with nontolerant animals. IFN-γ deficiency or anti–IFN-γ Ab treatment demonstrated that conversion to CXCR3+T-bet+ Tregs depended on a Th1 response. Accordingly, in an immunotherapeutic approach, CD4+CD25+Foxp3+ Tregs from Con A-pretreated CXCR3-deficient mice failed to protect against Con A-induced hepatitis, whereas Tregs from Con A-tolerant wt mice allowed CXCR3-deficient mice to recover from Con A hepatitis. In summary, CXCR3+T-bet+IL-10+ Tregs are generated in the liver in dependence of IFN-γ, then disseminated into the organism and specifically migrate into the liver, where they limit immune-mediated liver damage.

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Section: Discussionsupporting

confidence: 81%

CXCR3 Deficiency Exacerbates Liver Disease and Abrogates Tolerance in a Mouse Model of Immune-Mediated Hepatitis

Erhardt

Wegscheid

Claass

et al. 2011

The Journal of Immunology

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“…In addition, we also demonstrate that CX3CR1 expression within NKT sublineage cells is differentially regulated by development of the thymic microenvironment. In this study, NKT1 a thymocytes fail to upregulate CX3CR1 within thymi that lack a fully differentiated stromal cell compartment, but become developmentally redirected to traffic toward CXCR3 ligands such as CXCL10 (10). Surprisingly, this developmental niche is only observed for the NKT1 a subset, implying that a causal relationship exists between stromal cell differentiation and trafficking of NKT1 a thymocytes.…”

Section: Discussionmentioning

confidence: 71%

“…Furthermore, upregulation of CXCR3 within LTb-deficient NKT1 a thymocytes resulted in an enhanced migration index toward the CXCR3 ligand CXCL10 when compared with control migration indices (Fig. 5C), suggesting that LTa 1 b 2 -LTbR-dependent signaling regulates the CXCR3-dependent trafficking of NKT1 a thymocytes (10). In addition, increased intrathymic trafficking of CXCR3-expressing NKT1 a thymocytes is associated with the selective reduction of NKT1 a lymphocytes in the blood, spleen, and livers of Krt-5-cre; LTb F/F ;CX3CR1 gfp/wt mice relative to controls (Fig.…”

Section: Fractalkine Receptor Is Expressed By Inkt Rtes But Does Notmentioning

confidence: 99%

“…What has been examined are proposed roles for sphingosine-1-phosphate receptor 1 (8) and neuropilin-1 (9) during thymic egress, and a requirement for CXCR3 during thymic iNKT retention (10). In contrast, a large number of studies have highlighted the importance of lymphocyte trafficking during conventional thymocyte development.…”

Section: Nvariant Nkt (Inkt) Cells Constitute An Innate-like T Cellmentioning

confidence: 99%

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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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“…In contrast, the contribution of chemokines and/or integrins might be only subsidiary. Accordingly we did not detect any variations in the expression of CXCR3 (data not shown), which has been described as critical for the retention of iNKT cells in the thymus [84].…”

Section: Discussionmentioning

confidence: 80%

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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Cutting Edge: The Chemokine Receptor CXCR3 Retains Invariant NK T Cells in the Thymus

Cited by 37 publications

References 17 publications

CXCR3 Deficiency Exacerbates Liver Disease and Abrogates Tolerance in a Mouse Model of Immune-Mediated Hepatitis

CXCR3 Deficiency Exacerbates Liver Disease and Abrogates Tolerance in a Mouse Model of Immune-Mediated Hepatitis

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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