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Roquin Paralogs Differentially Regulate Functional NKT Cell Subsets Christoph Drees, J

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Roquin Paralogs Differentially Regulate Functional NKT Cell Subsets Christoph Drees, J Roquin Paralogs Differentially Regulate Functional NKT Cell Subsets Christoph Drees, J. Christoph Vahl, Sabrina Bortoluzzi, Klaus D. Heger, Julius C. Fischer, F. Thomas Wunderlich, This information is current as Christian Peschel and Marc Schmidt-Supprian of September 29, 2021. J Immunol published online 10 February 2017 http://www.jimmunol.org/content/early/2017/02/09/jimmun ol.1601732 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2017/02/09/jimmunol.160173 Material 2.DCSupplemental http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 29, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2017 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published February 10, 2017, doi:10.4049/jimmunol.1601732 The Journal of Immunology Roquin Paralogs Differentially Regulate Functional NKT Cell Subsets Christoph Drees,*,1,2 J. Christoph Vahl,†,1,3 Sabrina Bortoluzzi,*,1 Klaus D. Heger,*,†,4 Julius C. Fischer,* F. Thomas Wunderlich,‡ Christian Peschel,* and Marc Schmidt-Supprian*,† NKT cells represent a small subset of glycolipid-recognizing T cells that are heavily implicated in human allergic, autoimmune, and malignant diseases. In the thymus, precursor cells recognize self-glycolipids by virtue of their semi-invariant TCR, which triggers NKT cell lineage commitment and maturation. During their development, NKT cells are polarized into the NKT1, NKT2, and NKT17 subsets, defined through their cytokine-secretion patterns and the expression of key transcription factors. However, we have largely ignored how the differentiation into the NKT cell subsets is regulated. In this article, we describe the mRNA- binding Roquin-1 and -2 proteins as central regulators of murine NKT cell fate decisions. In the thymus, T cell–specific ablation of Downloaded from the Roquin paralogs leads to a dramatic expansion of NKT17 cells, whereas peripheral mature NKT cells are essentially absent. Roquin-1/2–deficient NKT17 cells show exaggerated lineage-specific expression of nearly all NKT17-defining proteins tested. We show through mixed bone marrow chimera experiments that NKT17 polarization is mediated through cell-intrinsic mechanisms early during NKT cell development. In contrast, the loss of peripheral NKT cells is due to cell-extrinsic factors. Surprisingly, Roquin paralog–deficient NKT cells are, in striking contrast to conventional T cells, compromised in their ability to secrete cytokines. Altogether, we show that Roquin paralogs regulate the development and function of NKT cell subsets in the thymus and http://www.jimmunol.org/ periphery. The Journal of Immunology, 2017, 198: 000–000. atural killer T cells express an evolutionarily conserved Rare Va14-Ja18 (Va14i) TCRa-chain rearrangements in CD4 semi-invariant TCR and are characterized by an activated CD8 double-positive (DP) thymocytes lead, in conjunction with a N phenotype and rapid secretion of effector cytokines limited number of TCRb-chains, to the expression of a glycolipid- in response to innate and antigenic stimulation. In the mouse, recognizing TCR. The overwhelming majority of NKT cells ex- NKT cells represent 0.2–0.5% of lymphocytes in thymus, spleen, press this Va14i-containing semi-invariant TCR. Therefore, they ∼ and bone marrow and 30% in the liver, whereas in humans the are termed invariant NKT or Va14i-NKT cells, but for simplicity by guest on September 29, 2021 fractions are smaller (,0.1 and 1%, respectively) (1). Despite we will refer to them as NKT cells. Recognition of glycolipid Ags their rarity, NKT cell responses can drive inflammation or toler- presented by CD1d on DP thymocytes through the semi-invariant ance, thereby impacting a wide range of immune cells, such as TCR expressed by precursor cells (stage 0: CD24high, CD44low, dendritic cells, NK cells, and B and T cells (2). NKT cells protect NK1.12) triggers NKT cell development (10, 11). These TCR their host organisms from certain strains of bacteria, sustain an- signals induce massive proliferative expansion, downregulation of tiviral responses, and contribute to the suppression of certain types CD24 (stage 1), and expression of the key transcriptional regu- of cancer and immune diseases (1, 3–6). In contrast, NKT cells are lator of NKT cell maturation, promyelocytic leukemia zinc fin- involved in the pathophysiology of allergic responses, ulcerative ger (PLZF) (12–15). Thymic NKT cell maturation is indicated by colitis, and liver cancer (7–9). Therefore, NKT cell activation can subsequent upregulation of the memory marker CD44 (stage 2) have dramatically different outcomes, depending on diverse en- and expression of NK cell markers, most prominently NK1.1 vironmental factors. (stage 3) (16, 17). While passing through stages 1–3, NKT cells *III. Medizinische Klinik fur€ Ha¨matologie und Onkologie, Klinikum Rechts der Isar, stipends from the Ernst Schering Foundation and the Boehringer Ingelheim Fonds, Technische Universita¨tMunchen,€ 81675 Munich, Germany; †Molecular Immunology respectively. and Signal Transduction Group, Max-Planck Institute of Biochemistry, 82152 Mar- C.D., J.C.V., S.B., and K.D.H. designed and performed experiments and analyzed tinsried, Germany; and ‡Obesity and Cancer Group, Max-Planck Institute for Meta- results; J.C.F. designed and performed experiments; F.T.W. provided essential re- bolism Research, 50931 Cologne, Germany agents and C.P. provided guidance; M.S.-S. designed the research and analyzed 1C.D., J.C.V., and S.B. contributed equally to this work and are considered first results; and C.D. and M.S.-S. wrote the article. authors. Address correspondence and reprint requests to Prof. Marc Schmidt-Supprian, De- 2Current address: Department of Internal Medicine III, Klinikum Grosshadern, partment of Hematology and Oncology, Klinikum rechts der Isar, Technische Uni- Munich, Germany. versita¨tMunchen,€ Ismaninger Strasse 22, 81675 Munchen,€ Germany. E-mail address: [email protected] 3Current address: Merck KGaA, Darmstadt, Germany. The online version of this article contains supplemental material. 4Current address: Physiological Chemistry, Genentech, Inc., South San Francisco, CA. Abbreviations used in this article: 7-AAD, 7-aminoactinomycin D; DN, double-negative; DP, double-positive; MFI, median fluorescence intensity; mLN, mesenteric lymph node; ORCIDs: 0000-0002-1683-8196 (J.C.V.); 0000-0002-6951-3416 (J.C.F.); 0000-0003- mTOR, mechanistic target of rapamycin; PLCg, phospholipase-Cg;pLN,peripheral 0547-2886 (C.P.). lymph node; PLZF, promyelocytic leukemia zinc finger; SLAM, signaling lymphocyte Received for publication October 6, 2016. Accepted for publication January 18, activation molecule; TFH, follicular Th; ThPOK, Th poxviruses and zinc finger and 2017. Kruppel€ family; TSC1, tuberous sclerosis 1. This work was supported by the Deutsche Forschungsgemeinschaft through Grants Ó SCHM2440-3 and SFB 1054 A02 (to M.S.-S.). J.C.V. and K.D.H. received Ph.D. Copyright 2017 by The American Association of Immunologists, Inc. 0022-1767/17/$30.00 www.jimmunol.org/cgi/doi/10.4049/jimmunol.1601732 2 ROQUIN PARALOGS POLARIZE NKT CELLS also differentiate into functional subsets termed NKT1 (PLZFlow, Samples were acquired on a FACSCanto II or LSRFortessa (BD) and T-bet+), NKT2 (PLZFhigh,GATA3+), and NKT17 (PLZFint, analyzed with FlowJo software. For gating on NKT cells, the following → RORgt+) cells, which are polarized toward the preferential pro- gating strategy was used: singlets LIVE/DEAD stain, gated on living cells → lymphocyte gate → TCRbint mCD1d-PBS57+ cells. NKT cell duction of cytokines reminiscent of the respective Th cell lineages stages and subsets were gated as indicated in the FACS plots. To ana- (18, 19). The signals and events that drive the differentiation of lyze the relative expression of extracellular and intracellular proteins, these NKT cell subsets are incompletely understood. median fluorescent intensities (MFIs) were calculated, and the mean MFI 2 + Roquin-1 and its mammalian paralog Roquin-2, encoded by of mCD1d-PBS57 tetramer TCRb T cells of the respective control mice was set to 1. rc3h1 and rc3h2 respectively, are mRNA-binding proteins that repress immune reactions by redundant and unique posttran- Isolation of lamina propria and lung lymphocytes scriptional regulation of genes, including costimulatory molecules For isolation of lamina propria lymphocytes, Peyer’s patches and fat tissue and proinflammatory cytokines (20–24). Thereby, these proteins were removed, and intestines were flushed with ice-cold PBS. Intestines act as safeguards against autoimmunity by preventing the spon- were opened longitudinally and cut into 1–1.5-cm pieces. After vigorously vortexing in PBS, samples were incubated two times for 15–20 min at taneous generation of follicular Th (TFH) cells, IL-17–producing Th17 cells, and IFN-g–producing
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