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Nur77 controls tolerance induction, terminal differentiation, and effector functions in semi-invariant natural killer T cells

Kumar, Amrendra and Hill, Timothy M. and Gordy, Laura E. and Suryadevara, Naveenchandra and Wu, Lan and Flyak, Andrew I. and Bezbradica, Jelena S. and Van Kaer, Luc and Joyce, Sebastian (2020) Nur77 controls tolerance induction, terminal differentiation, and effector functions in semi-invariant natural killer T cells. Proceedings of the National Academy of Sciences of the United States of America, 117 (29). pp. 17156-17165. ISSN 0027-8424. PMCID PMC7382224. https://resolver.caltech.edu/CaltechAUTHORS:20200702-094429739

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Abstract

Semi-invariant natural killer T (iNKT) cells are self-reactive lymphocytes, yet how this lineage attains self-tolerance remains unknown. iNKT cells constitutively express high levels of Nr4a1-encoded Nur77, a transcription factor that integrates signal strength downstream of the T cell receptor (TCR) within activated thymocytes and peripheral T cells. The function of Nur77 in iNKT cells is unknown. Here we report that sustained Nur77 overexpression (Nur77^(tg)) in mouse thymocytes abrogates iNKT cell development. Introgression of a rearranged Vα14-Jα18 TCR-α chain gene into the Nur77^(tg) (Nur77^(tg);Vα14^(tg)) mouse rescued iNKT cell development up to the early precursor stage, stage 0. iNKT cells in bone marrow chimeras that reconstituted thymic cellularity developed beyond stage 0 precursors and yielded IL-4–producing NKT2 cell subset but not IFN-γ–producing NKT1 cell subset. Nonetheless, the developing thymic iNKT cells that emerged in these chimeras expressed the exhaustion marker PD1 and responded poorly to a strong glycolipid agonist. Thus, Nur77 integrates signals emanating from the TCR to control thymic iNKT cell tolerance induction, terminal differentiation, and effector functions.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1073/pnas.2001665117DOIArticle
https://www.pnas.org/content/suppl/2020/06/30/2001665117.DCSupplementalPublisherSupporting Information
http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7382224/PubMed CentralArticle
ORCID:
AuthorORCID
Kumar, Amrendra0000-0002-1191-5228
Hill, Timothy M.0000-0001-7658-811X
Gordy, Laura E.0000-0002-3736-2932
Suryadevara, Naveenchandra0000-0003-2571-1290
Wu, Lan0000-0001-6032-083X
Flyak, Andrew I.0000-0002-8722-479X
Bezbradica, Jelena S.0000-0003-1441-1727
Van Kaer, Luc0000-0001-5275-2309
Joyce, Sebastian0000-0002-3183-1451
Additional Information:© 2020 National Academy of Sciences. Published under the PNAS license. Edited by Philippa Marrack, National Jewish Health, Denver, CO, and approved June 2, 2020 (received for review January 28, 2020). PNAS first published July 1, 2020. We thank Drs. A. Winoto (University of California Berkeley) and M. Taniguchi (RIKEN, Japan) for the B6- B6-Nur77^(tg) (Nur77^(tg)) and B6-Jα18^(−/−) (Jα18^(−/−)) mice, respectively. We also thank A. J. Joyce for maintaining our mouse colony. We thank Vanderbilt University Medical Centre Flow Cytometry Shared Resources, supported by Vanderbilt Ingram Cancer Center (CA68485), and the NIH Tetramer Core, for the CD1d-αGC tetramer. This work was supported by NIH Grants AI137082, AI061721, and AI042284 (to S.J.), DK081536 (to L.W. and L.V.K.), and DK104817 and AI139046 (to L.V.K.); American Heart Association Grant 19TPA34910078 (to L.V.K.); and VA Merit Award BX001444 (to S.J.). Data Availability: All data are presented in the main figures and supplemental figures. Raw data and replicates are available from the corresponding author on request. Author contributions: A.K., T.M.H., L.E.G., L.W., J.S.B., and S.J. designed research; A.K., T.M.H., L.E.G., N.S., L.W., A.I.F., and J.S.B. performed research; L.V.K. contributed new reagents/analytic tools; A.K., T.M.H., L.E.G., A.I.F., J.S.B., and S.J. analyzed data; and A.K. and S.J. wrote the paper. The authors declare no competing interest. This article is a PNAS Direct Submission. This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2001665117/-/DCSupplemental.
Funders:
Funding AgencyGrant Number
NIHCA68485
Vanderbilt Ingram Cancer CenterUNSPECIFIED
NIHAI137082
NIHAI061721
NIHAI042284
NIHDK081536
NIHDK104817
NIHAI139046
American Heart Association19TPA34910078
Department of Veterans AffairsBX001444
Subject Keywords:iNKT cells; development; function; Nur77
Issue or Number:29
PubMed Central ID:PMC7382224
Record Number:CaltechAUTHORS:20200702-094429739
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20200702-094429739
Official Citation:Nur77 controls tolerance induction, terminal differentiation, and effector functions in semi-invariant natural killer T cells. Amrendra Kumar, Timothy M. Hill, Laura E. Gordy, Naveenchandra Suryadevara, Lan Wu, Andrew I. Flyak, Jelena S. Bezbradica, Luc Van Kaer, Sebastian Joyce. Proceedings of the National Academy of Sciences Jul 2020, 117 (29) 17156-17165; DOI: 10.1073/pnas.2001665117
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:104203
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:02 Jul 2020 17:20
Last Modified:05 Aug 2020 21:46

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