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Development Multiple Checkpoints in Invariant NKT Cell Essential Essential Functions for ID Proteins at Multiple Checkpoints in Invariant NKT Cell Development This information is current as Mihalis Verykokakis, Veena Krishnamoorthy, Antonio of September 27, 2021. Iavarone, Anna Lasorella, Mikael Sigvardsson and Barbara L. Kee J Immunol 2013; 191:5973-5983; Prepublished online 15 November 2013; doi: 10.4049/jimmunol.1301521 Downloaded from http://www.jimmunol.org/content/191/12/5973 Supplementary http://www.jimmunol.org/content/suppl/2013/11/18/jimmunol.130152 Material 1.DC1 http://www.jimmunol.org/ References This article cites 52 articles, 22 of which you can access for free at: http://www.jimmunol.org/content/191/12/5973.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 27, 2021 • 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 © 2013 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Essential Functions for ID Proteins at Multiple Checkpoints in Invariant NKT Cell Development Mihalis Verykokakis,*,† Veena Krishnamoorthy,* Antonio Iavarone,‡,x,{ Anna Lasorella,‡,x,{ Mikael Sigvardsson,‖ and Barbara L. Kee*,† Invariant NKT (iNKT) cells display characteristics of both adaptive and innate lymphoid cells (ILCs). Like other ILCs, iNKT cells constitutively express ID proteins, which antagonize the E protein transcription factors that are essential for adaptive lymphocyte development. However, unlike ILCs, ID2 is not essential for thymic iNKT cell development. In this study, we demonstrated that ID2 and ID3 redundantly promoted iNKT cell lineage specification involving the induction of the signature transcription factor PLZF and that ID3 was critical for development of TBET-dependent NKT1 cells. In contrast, both ID2 and ID3 limited iNKT cell numbers by enforcing the postselection checkpoint in conventional thymocytes. Therefore, iNKT cells show both adaptive and innate-like requirements for ID proteins at distinct checkpoints during iNKT cell development. The Journal of Immunology, Downloaded from 2013, 191: 5973–5983. atural killer T cells are T lymphocytes that display the Tcra locus and are recombined through secondary rearrange- characteristics of innate immune cells, including the use ments that occur late in the life of CD4+CD8+ (double-positive N of invariant receptors to recognize pathogen and rapid [DP]) thymocytes (5). Mice harboring mutations that decrease DP activation without prior Ag exposure. NKT cells diverge from the thymocyte survival and mice with limited Tcra recombination http://www.jimmunol.org/ conventional T cell program during positive selection. Following lack iNKT cells (6–8). Positive selection of iNKT cells requires selection, NKT cell maturation is coupled with the ability to rapidly lipid Ag presentation by the nonclassical MHC class I protein CD1d secrete cytokines when challenged (1). As a consequence of their expressed on DP thymocytes, along with signals from the signaling “poised” effector state and ability to produce numerous cytokines, lymphocyte activation molecule (SLAM) family receptors (9, 10). NKT cells can act as both positive and negative regulators of an This selection pathway results in the TCR-dependent induction of immune response. They promote pathogen and tumor clearance, the lineage-specifying transcription factor promyelocytic leukemia but their activity can contribute to diseases such as autoimmunity, zinc finger (PLZF), which is essential for iNKT development and atherosclerosis, and asthma (2, 3). To harness the therapeutic potential confers innate properties to conventional CD4 T cells when ectop- of NKT cells, a comprehensive understanding of the mechanisms ically expressed (11–14). by guest on September 27, 2021 controlling NKT cell selection, maturation, and effector function is iNKT cell maturation is divided into four stages, based on the required. surface expression of CD24, CD44, and NK1.1 (15, 16). Stage 2 2 Invariant NKT (iNKT) cells, characterized by a Va14-Ja18 0 (CD24+CD44 NK1.1 ) represents rare iNKT cell precursors TCRa-chain paired with TCR Vb7, Vb8, and Vb2 chains (4), are among postselection (PS) DP thymocytes. Stage 1 cells down- the most abundant and well-characterized NKT cell population in regulate CD8 and CD24 and express low levels of the memory mice. The Va14 and Ja18 gene segments are located far apart in marker CD44. Stage 2 cells have increased CD44 and can progress tostage3inthethymus,wheretheyexpressseveralNKcell receptors including NK1.1, or they can exit the thymus and mature *Department of Pathology, University of Chicago, Chicago, IL 60637; †Committee on further in the peripheral tissues. Stage 2 iNKT cells have been ‡ Immunology, University of Chicago, Chicago, IL 60637; Institute for Cancer Genet- considered an immature stage, although these cells can robustly ics, Columbia University Medical Center, New York, NY 10032; xDepartment of Neurology, Columbia University Medical Center, New York, NY 10032; {Department produce both Th1 and Th2 cytokines. However, a subset of stage of Pathology, Columbia University Medical Center, New York, NY 10032; and ‖Ex- 2 iNKT cells are terminally differentiated cells that express the perimental Hematopoiesis Unit, Department of Clinical and Experimental Medicine, transcription factor GATA3, and these have been classified recently Faculty for Health Sciences, Linko¨ping University, 58183 Linko¨ping, Sweden as NKT2 cells. Stage 3 iNKT cells preferentially produce the Th1 Received for publication June 12, 2013. Accepted for publication October 9, 2013. cytokine IFN-g with lower amounts of Th2 cytokines and have been This work was supported by National Institutes of Health Grant CA099978 (to B.L.K.). B.L.K. is a scholar of the Leukemia and Lymphoma Society. classified as NKT1 (17). TBET is critical for the maturation, sur- vival, and Th1-like characteristics of NKT1 (18, 19). Therefore, The sequence data presented in this article have been submitted to the Gene Expres- sion Omnibus (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc) under accession acquisition of an iNKT cell TCR and induction of PLZF and TBET number GSE50933. define three critical checkpoints during iNKT cell development that Address correspondence and reprint requests to Dr. Barbara L. Kee and Dr. Mihalis control their abundance and functional competence. Verykokakis, Department of Pathology, University of Chicago, 924 East 57th Street, The E protein transcription factors are important regulators of JFK, Room R318, Chicago, IL 60637. E-mail addresses: [email protected] (B.L.K.) and [email protected] (M.V.) conventional T cell development and selection, and they control the The online version of this article contains supplemental material. life span and gene signature of DP thymocytes (20, 21). E protein Abbreviations used in this article: BM, bone marrow; DP, double-positive; ILC, function can be modulated through antagonistic interactions with innate lymphoid cell; iNKT, invariant NKT; LMC, littermate control; PLZF, promye- any of the four members of the ID family (ID1–4) (22). TCR- locytic leukemia zinc finger; PS, postselection; qPCR, quantitative PCR; SLAM, dependent induction of ID3, and the consequent decrease in E signaling lymphocyte activation molecule; Tet, tetramer; WT, wild-type. protein activity, is critical for positive selection of conventional Copyright Ó 2013 by The American Association of Immunologists, Inc. 0022-1767/13/$16.00 CD4 and CD8 T lymphocytes (23–25). However, a role for ID3 in www.jimmunol.org/cgi/doi/10.4049/jimmunol.1301521 5974 ID PROTEINS CONTROL iNKT CELL DEVELOPMENT the TCR-dependent selection of iNKT cells has not been dem- Cell culture, IFN-g/IL-4 production, and intracellular staining onstrated. Moreover, although development of all non-T cell line- Thymocytes were treated with 50 ng PMA, 1 mg ionomycin, and brefeldin age innate lymphoid cells (ILC) depends on the ID2 protein (26), A for 5 h, before harvesting and staining intracellularly for IFN-g and IL-4 thymic development of iNKT cells appears to be independent of using the BD Biosciences Cytofix/Cytoperm kit. ID2 (27). Why iNKT cells differ from other ILCs in their re- RNA analysis and real-time quantitative PCR quirement for ID2 remains to be determined. We and others (28–31) recently demonstrated that ID3 restricts Total RNA was extracted and DNAase-treated from sorted thymocytes us- the development of ab and gd NKT-like cells. In this study, we ing the RNAeasy Mini Kit (Qiagen) and was reverse transcribed using Superscript III (Invitrogen). Quantitative PCR (qPCR) was performed with showed that ID proteins were central regulators of the three major gene-specific primers in an iCycler (Bio-Rad), using the iQ SYBR Green thymic iNKT cell developmental checkpoints. ID proteins limited Supermix (Bio-Rad). Hypoxanthine phosphoribosyltransferase was used to selection
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