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IL-1Β and IL-23 Promote Extrathymic Commitment of CD27+CD122

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IL-1Β and IL-23 Promote Extrathymic Commitment of CD27+CD122 IL-1β and IL-23 Promote Extrathymic Commitment of CD27 +CD122− δγ T Cells to δγ T17 Cells This information is current as Andreas Muschaweckh, Franziska Petermann and Thomas of September 27, 2021. Korn J Immunol published online 30 August 2017 http://www.jimmunol.org/content/early/2017/08/30/jimmun ol.1700287 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2017/08/30/jimmunol.170028 Material 7.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 27, 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 Author Choice Freely available online through The Journal of Immunology Author Choice option 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 August 30, 2017, doi:10.4049/jimmunol.1700287 The Journal of Immunology IL-1b and IL-23 Promote Extrathymic Commitment of CD27+CD1222 gd T Cells to gdT17 Cells Andreas Muschaweckh,*,1 Franziska Petermann,*,1,2 and Thomas Korn*,† gdT17 cells are a subset of gd T cells committed to IL-17 production and are characterized by the expression of IL-23R and CCR6 and lack of CD27 expression. gdT17 cells are believed to arise within a narrow time window during prenatal thymic development. In agreement with this concept, we show in this study that adult Rag12/2 recipient mice of Il23rgfp/+ (IL-23R reporter) bone marrow selectively lack IL-23R+ gdT17 cells. Despite their absence in secondary lymphoid tissues during homeostasis, gdT17 cells emerge in bone marrow chimeric mice upon induction of skin inflammation by topical treatment with imiquimod cream (Aldara). We demonstrate that IL-1b and IL-23 together are able to promote the development of bona fide gdT17 cells from peripheral CD1222IL-23R2 gd T cells, whereas CD122+ gd T cells fail to convert into gdT17 cells and remain stable IFN-g producers (gdT1 + cells). IL-23 is instrumental in expanding extrathymically generated gdT17 cells. In particular, TCR-Vg4 chain–expressing Downloaded from CD1222IL-23R2 gd T cells are induced to express IL-23R and IL-17 outside the thymus during skin inflammation. In contrast, TCR-Vg1+ gd T cells largely resist this process because prior TCR engagement in the thymus has initiated their commitment to the gdT1 lineage. In summary, our data reveal that the peripheral pool of gd T cells retains a considerable degree of plasticity because it harbors “naive” precursors, which can be induced to produce IL-17 and replenish peripheral niches that are usually occupied by thymus-derived gdT17 cells. The Journal of Immunology, 2017, 199: 000–000. http://www.jimmunol.org/ unctional phenotypes of gd T cells, i.e., IFN-g–producing Thus, other cues, including Notch-dependent pathways but also gdT1 cells and IL-17–producing gdT17 cells, are gener- cytokine signals, might be determinants of gdT17 commitment. F ated during thymic development. gdT17 cells can be For example, the Notch–Hes1 pathway and the noncanonical identified by a series of surface markers. IL-23R expression (RelB) NF-kB pathway as well as, in a gd thymocyte–extrinsic strictly segregates with IL-17 expression in gd T cells (1). In manner, NIK and RelA expression in the thymus are required for addition, all IL-17–producing gd T cells are contained within the the generation of gdT17 cells (6–8). In contrast, IRF4, which is 2 CD27 gd T cell compartment and express CCR6 (2, 3). Whether critically required for Th17 cell differentiation, is dispensable for a thymocyte is committed to the gdT1 versus the gdT17 lineage is the development of gdT17 cells (9). Although probably irrelevant most likely dependent on various cues. gd TCR engagement has for the de novo generation of gdT17 cells in the thymus, STAT3 is by guest on September 27, 2021 been suggested to dictate the commitment of thymocytes to the required for the expansion of gdT17 cells, and the selective ex- gdT1 lineage (4). In contrast, gdT17 cell development appears to pansion of gdT17 cells by IL-7 was reported to depend on STAT3 be independent of TCR engagement as IL-17 production is de- (10). In contrast, IL-17 production most likely from ab thymo- tected in a subset of thymocytes that are poised to become gd cytes might negatively regulate gdT17 generation and was pro- T cells but have not yet rearranged their d and g TCR genes (5). posed to be responsible for shutting down gdT17 generation in the adult thymus (5). Once exported from the thymus, gdT1 cells and gdT17 cells *Klinikum Rechts der Isar, Neurologische Klinik, Technische Universita¨tMunchen,€ populate secondary lymphoid organs and certain peripheral tissue † 81675 Munich, Germany; and Munich Cluster for Systems Neurology (SyNergy), niches. For example, the dermis harbors gdT17 cells that expand 81377 Munich, Germany 1 upon exposure of the skin to imiquimod cream (Aldara) and cause A.M. and F.P. contributed equally to this work. a psoriasis-like pathology (11). Recently, it was demonstrated that 2 Current address: Lymphocyte Cell Biology Section, National Institute of Arthritis early after birth, the dermis mostly contains TCR-Vg6+ gdT17 and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD. cells, whereas in adult individuals more TCR-Vg4+ than TCR- ORCIDs: 0000-0002-6870-1378 (A.M.); 0000-0002-3145-2304 (F.P.); 0000-0002- + + 3633-0955 (T.K.). Vg6 gdT17 cells populate the dermis (12). TCR-Vg6 gdT17 Received for publication February 23, 2017. Accepted for publication August 4, cells are thymically imprinted to home to the dermis, whereas 2017. TCR-Vg4+ gdT17 cells acquire their skin-homing properties T.K. was supported by a Heisenberg award from the Deutsche Forschungsgemein- extrathymically. Yet, both subsets of dermal gd T cells are pre- schaft (KO2964/3-2 Heisenberg Sachbeihilfe). This work was supported by the imprinted to produce IL-17 and not IFN-g. gdT17 cells exhibit a Deutsche Forschungsgemeinschaft (SFB1054/B06, TR128/A06, A07), the European Research Council (CoG 647215), and within the framework of the Munich Cluster permissive epigenetic landscape and can convert into IFN-g pro- for Systems Neurology (SyNergy) (EXC 1010). ducers in vitro and in vivo in the context of distinct inflamma- Address correspondence and reprint requests to Dr. Thomas Korn, Klinikum Rechts tory environments (13). In contrast, IFN-g–producing gdT1 cells der Isar, Neurologische Klinik, Technische Universita¨tMunchen,€ Ismaninger Strasse have been proposed to exhibit an epigenetic signature indica- 22, 81675 Munich, Germany. E-mail address: [email protected] tive of a “terminally committed” phenotype which precludes The online version of this article contains supplemental material. plasticity to convert into IL-17 producers (13). It is commonly Abbreviation used in this article: DN, double negative. believed that gdT17 cells develop in the thymus during an early This article is distributed under The American Association of Immunologists, Inc., ontogenetic window shortly before birth and, therefore, the Reuse Terms and Conditions for Author Choice articles. possibility of a secondary de novo generation of gdT17 cells Copyright Ó 2017 by The American Association of Immunologists, Inc. 0022-1767/17/$35.00 outside the thymus has thus far been dismissed. Rather, it is www.jimmunol.org/cgi/doi/10.4049/jimmunol.1700287 2 EXTRATHYMIC DIFFERENTIATION OF gdT17 CELLS thought that postnatally, the initial pool of gdT17 cells is main- Flow cytometry tained through self-renewal, perhaps in response to homeostatic cy- Single-cell suspensions were incubated with Fc-blocking Abs (aCD16/ tokine cues including IL-7 (10). aCD32; BD Biosciences) and subsequently stained with 1:100 dilutions of gdT17 cells have most recently been shown to participate in the the respective surface marker Abs for 30 min at 4˚C. Staining was carried immunopathology of a variety of inflammatory diseases in epi- out with Abs to CD3 (145-2C11), CD4 (RM4-5), and CD27 (LG.3A10) thelial barrier tissues, including inflammatory bowel disease, from BD Biosciences; CD45.1 (A20), CD45.2 (104), and CD122 (TM-b1) from eBioscience; CCR6 (140706, R&D), TCR gd (GL-3), TCR-Vg1 psoriasis, and asthma (11, 14, 15), but also in spondylarthropathies (2.11), and TCR-Vg4 (UC3-10A6) from BioLegend. The Tonegawa no- and CNS inflammation in mouse models (1, 16) and in humans menclature was used to designate TCR-Vg chains throughout the text. The (17–19). Because the presence of gdT17 cells in certain tissues staining panels always included dead cell staining dyes (7-AAD [BD might set the threshold for these tissues to respond directly to Biosciences] or Aqua [Invitrogen]). After staining, cells were washed and analyzed using a CyAn FACS machine (Beckman Coulter) or a BD pathogen-associated molecular patterns and indirectly to the FACSAria III (BD Biosciences). proinflammatory cytokine IL-23, the regulation of gdT17 cell populations during homeostasis and in inflammation is highly Intracellular cytokine and transcription factor staining relevant in the context of immune interventions in autoimmune Cells were stimulated in culture medium containing PMA (50 ng/ml; diseases, chronic inflammation, and inflammation associated with Sigma), ionomycin (1 mg/ml; Sigma-Aldrich), and monensin (GolgiStop, malignant disease. In this study, we show that under homeostatic 1 ml/ml; BD Biosciences) at 37˚C and 10% CO2 for 4 h.
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