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Monoclonal Invariant Monoclonal Invariant NKT (iNKT) Cell Mice Reveal a Role for Both Tissue of Origin and the TCR in Development of iNKT Functional Subsets This information is current as of October 29, 2020. Eleanor Clancy-Thompson, Gui Zhen Chen, Paul M. Tyler, Mariah M. Servos, Marta Barisa, Patrick J. Brennan, Hidde L. Ploegh and Stephanie K. Dougan J Immunol 2017; 199:159-171; Prepublished online 2 June 2017; Downloaded from doi: 10.4049/jimmunol.1700214 http://www.jimmunol.org/content/199/1/159 Supplementary http://www.jimmunol.org/content/suppl/2017/05/31/jimmunol.170021 http://www.jimmunol.org/ Material 4.DCSupplemental References This article cites 58 articles, 28 of which you can access for free at: http://www.jimmunol.org/content/199/1/159.full#ref-list-1 Why The JI? Submit online. by guest on October 29, 2020 • 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 *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. The Journal of Immunology Monoclonal Invariant NKT (iNKT) Cell Mice Reveal a Role for Both Tissue of Origin and the TCR in Development of iNKT Functional Subsets Eleanor Clancy-Thompson,* Gui Zhen Chen,* Paul M. Tyler,* Mariah M. Servos,* Marta Barisa,† Patrick J. Brennan,‡ Hidde L. Ploegh,†,1 and Stephanie K. Dougan*,†,1 Invariant NKT (iNKT) cell functional subsets are defined by key transcription factors and output of cytokines, such as IL-4, IFN-g, IL-17, and IL-10. To examine how TCR specificity determines iNKT function, we used somatic cell nuclear transfer to generate three lines of mice cloned from iNKT nuclei. Each line uses the invariant Va14Ja18 TCRa paired with unique Vb7orVb8.2 subunits. We examined tissue homing, expression of PLZF, T-bet, and RORgt, and cytokine profiles and found that, although monoclonal iNKT cells differentiated into all functional subsets, the NKT17 lineage was reduced or expanded depending on the Downloaded from TCR expressed. We examined iNKT thymic development in limited-dilution bone marrow chimeras and show that higher TCR avidity correlates with higher PLZF and reduced T-bet expression. iNKT functional subsets showed distinct tissue distribution patterns. Although each individual monoclonal TCR showed an inherent subset distribution preference that was evident across all tissues examined, the iNKT cytokine profile differed more by tissue of origin than by TCR specificity. The Journal of Immunology, 2017, 199: 159–171. KT cells are a subset of T cells that primarily recognize inflammation, iNKT cells can skew the ensuing immune response http://www.jimmunol.org/ lipid Ags in a complex with the class I MHC homolog by rapidly producing cytokines, such as IFN-g, IL-13, and IL-4, N CD1d (1, 2). Type II NKT cells carry a diverse TCR without an obligate need for proliferation (1). repertoire, recognize a variety of lipid Ags, such as sulfatides, and Functional subsets of iNKT cells exist, and they are classified will not be discussed further in this article. In mice, type I according to the expression of signature transcription factors during NKT cells (invariant NKT [iNKT]) express an invariant thymic development or by the production of signature cytokines. Va14Ja18 TCRa-chain, paired with a limited, but diverse, set of T-bet, PLZF, and RORgt delineate NKT1, NKT2, and NKT17 TCRb-chains. Vb8.1, 8.2, 7, 8.3, and 2 are preferentially used, but subsets in the thymus; they produce IFN-g, IL-4, or IL-17, re- the CDR3 regions vary widely, such that iNKT cells form a spectively (6–8). The three major iNKT cell subsets likely dif- by guest on October 29, 2020 polyclonal pool (3). iNKT cells are activated by the ligand ferentiate during thymic development, as most convincingly a-galactosylceramide (a-GalCer) (1, 4). Other known Ags include shown by single-cell transcriptional profiling of thymic NKT1, self- and microbial lipids (5). Under conditions of infection or NKT2, NKT17, and NKT0 cells (9). Whether interconversions among iNKT subsets can occur is not known. Production of NKT17 cells appears to be driven by particular signaling path- *Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, ways; ThPOK and PTEN expression inversely correlate with ac- Boston, MA 02215; †Whitehead Institute for Biomedical Research, Cambridge, quisition of a RORgt+ IL-17–producing phenotype (10, 11), MA 02242; and ‡Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital, Boston, MA 02215 whereas mTORC2 is required for NKT17 development (12). Oxidized 5 methylcytosine in DNA suppresses NKT17 develop- 1H.L.P. and S.K.D. contributed equally to this work. ment, as revealed by an overabundance of hyperactivated NKT17 ORCIDs: 0000-0002-5483-7178 (G.Z.C.); 0000-0001-7846-6810 (M.B.). cells in mice lacking the epigenetic regulators Tet2 and Tet3 (13). Received for publication February 10, 2017. Accepted for publication May 2, 2017. Other subsets of iNKT cells, including IL-10–producing NKT10 E.C.-T. was funded by National Institutes of Health Grant T32CA207021. P.J.B. was cells (14), follicular helper-like iNKT cells (15), IL-9–producing funded by National Institutes of Health Grant AI102945. S.K.D. was funded by the Bushrod H. Campbell and Adah F. Hall Charity Fund, the Harold Whitworth Pierce iNKT cells (16), and regulatory iNKT cells (11, 17) have been Charitable Trust, the Melanoma Research Alliance, and the Claudia Adams Barr described, but there is no evidence for thymic instruction of these Program in Cancer Research. S.K.D. and H.L.P. were funded by Janssen Pharma- ceutical, Inc. subsets. Certain iNKT subsets are enriched in particular tissues; adipose tissue contains PLZF2E4BP4+ IL-10–producing E.C.-T. designed and conducted experiments, analyzed data, and helped to write the manuscript; G.Z.C., P.M.T., M.M.S., and M.B. conducted experiments; P.J.B. sup- iNKT cells with a regulatory phenotype (18, 19), whereas skin- plied a-glucosylceramide and OCH tetramers and contributed to data interpretation; draining lymph nodes are enriched in NK1.12CD42CD44+ S.K.D. generated the mouse lines; and H.L.P. and S.K.D. designed experiments, analyzed data, and wrote the manuscript. NKT17 cells (20, 21). NKT2 cells are more frequently found in mesenteric lymph nodes, at least in BALB/c mice (7). In a model Address correspondence and reprint requests to Dr. Stephanie K. Dougan, Dana-Farber Cancer Institute, 450 Brookline Avenue, Sm770A, Boston, MA 02215. E-mail address: of tuberculosis infection, iNKT cells producing GM-CSF were [email protected] crucial for control of infection in the lung (22). Liver-resident and The online version of this article contains supplemental material. spleen-resident iNKT cells differ in their ability to reject B16 Abbreviations used in this article: cat. no., catalog number; a-GalCer, a-galactosylcer- melanoma lung metastases (23). amide; a-Glc, a-glucosylceramide; iNKT, invariant NKT; NIH, National Institutes of Recognition of a-GalCer occurs predominantly through the Health; SCNT, somatic cell nuclear transfer; TN, transnuclear; Treg, regulatory T cell. TCRa-chain, with the TCRb-chain forming contacts only with Copyright Ó 2017 by The American Association of Immunologists, Inc. 0022-1767/17/$30.00 CD1d (24). Nevertheless, Vb-chain usage may influence the www.jimmunol.org/cgi/doi/10.4049/jimmunol.1700214 160 MONOCLONAL iNKT CELLS SHOW SUBSET PREFERENCE spectrum of ligands recognized by iNKT cells (25). Cocrystal mice (nine generations for RAG22/2 crossed lines). F1 mice were gen- structures of TCR, ligand, and CD1d, together with careful mea- erated by crossing seven-generation C57BL/6-backcrossed males to surements of binding kinetics, suggest that ligand merely deter- BALB/c females. Va14 mice used throughout the study were littermates of the Vb7A, Vb7C, or Vb8.2 mice used. Mice were used at 6–12 wk of age, mines the off-rate of TCR binding (26–29). Indeed, in contrast to and both males and females were included. For each experiment, five mice most class I MHC–restricted TCRs, the iNKT TCR adopts a were included per group. A mix of ages and both sexes were included per similar docking mode independent of the identity of the ligand group, with age and sex matching among the groups as closely as possible. bound (30–33). In contrast, a library of recombinant iNKT TCRs No correlation was observed between age and any of the parameters ex- amined or sex and any of the parameters examined. with different TCRb-chains showed differential recognition of molecules such as iGb3, GSL-1, and other ligands thought to be Sequencing of the TCR genes more physiologically relevant than a-GalCer (34). Similar effects + iNKT cells were sorted by FACS for CD1d-PBS57 tetramer cells and used of TCRb mutations on ligand recognition were observed for hu- as a source of RNA. 59RACE was performed according to the manufac- man iNKT TCRs (35), and indeed, selective loss of high-affinity turer’s protocol (Number L1502-01, GeneRacer; Invitrogen). Gene se- iNKT cells has been observed in several human diseases (36, 37). quences were searched against the IEDB database (http://www.iedb.org).
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