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Enhances IL-5 Production T Cell Activation + Acid During CD4 Retinoic Trans LZTFL1 Upregulated By LZTFL1 Upregulated by All-Trans Retinoic Acid during CD4 + T Cell Activation Enhances IL-5 Production This information is current as Hong Jiang, Kanyarat Promchan, Bor-Ruei Lin, Stephen of September 25, 2021. Lockett, De Chen, Heather Marshall, Yunden Badralmaa and Ven Natarajan J Immunol 2016; 196:1081-1090; Prepublished online 23 December 2015; doi: 10.4049/jimmunol.1500719 Downloaded from http://www.jimmunol.org/content/196/3/1081 Supplementary http://www.jimmunol.org/content/suppl/2015/12/23/jimmunol.150071 Material 9.DCSupplemental http://www.jimmunol.org/ References This article cites 64 articles, 23 of which you can access for free at: http://www.jimmunol.org/content/196/3/1081.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 25, 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 © 2016 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology LZTFL1 Upregulated by All-Trans Retinoic Acid during CD4+ T Cell Activation Enhances IL-5 Production Hong Jiang,*,1 Kanyarat Promchan,* Bor-Ruei Lin,* Stephen Lockett,† De Chen,† Heather Marshall,* Yunden Badralmaa,* and Ven Natarajan* Retinoic acids, which are metabolites of vitamin A, have been shown to be involved in multiple T cell effector responses through their binding to the retinoic acid receptor, a ligand-activated transcription factor. Because the molecular mechanism of regulation by retinoic acid is still not fully uncovered, we investigated the gene expression profile of all-trans retinoic acid (ATRA)–treated human CD4+ T cells. Leucine zipper transcription factor-like 1 (LZTFL1) was upregulated by ATRA in a dose- and time-dependent manner. The expression of LZTFL1 depended on both ATRA and TCR signaling. LZTFL1 accumulated in the plasma membrane compartment of human CD4+ T cells, and, during immunological synapse formation, it transiently redistributed to the T cell and APC contact zone, indicating its role in T cell activation. Live-cell imaging demonstrates that at the initial stage of immunological Downloaded from synapse formation, LZTFL1 is concentrated at the APC contact site, and, during later stages, it relocates to the distal pole. Knockdown of LZTFL1 reduced the basal- and ATRA-induced levels of IL-5 in CD4+ T cells, and overexpression of LZTFL1 enhanced the TCR-mediated NFAT signaling, suggesting that LZTFL1 is an important regulator of ATRA-induced T cell re- sponse. Together, these data indicate that LZTFL1 modulates T cell activation and IL-5 levels. The Journal of Immunology, 2016, 196: 1081–1090. http://www.jimmunol.org/ etinoic acids (RAs), especially all-trans RA (ATRA), the mice given a vitamin A or RA supplement showed decreased active metabolite of vitamin A, are known to regulate production of the Th1 cytokine IFN-g and increased production of R cell differentiation, proliferation, and apoptosis in a va- Th2 cytokines IL-4, -IL-5, and -IL-13 (15). Even though the riety of cell types through their binding to the RA receptor (RAR), mechanism of RAs’ impact on Th2 cell development is still not a ligand-activated transcription factor (1, 2). Vitamin A and RAs fully understood, the direct and indirect effects of RAs have been influence T cell function in many ways, including peripheral T cell suggested. By inhibiting IL-12 production in activated macro- differentiation, gut-homing capacity, and effector T cell activity phages, RA pretreatment of macrophages reduced IFN-g pro- (3–8). RAs are known to favor Th2 cell development (8–14). duction and increased IL-4 production in Ag-primed CD4+ T cells Vitamin A deficiency causes immune dysfunction, including IFN-g (18), and stimulating Ab-primed human PBMCs and purified by guest on September 25, 2021 overproduction and impaired Ab responses, which is the result of T cells with RAs in vitro directly increased the mRNA and protein excess Th1 and insufficient Th2 function (15, 16). Vitamin A– levels of IL-4, IL-5, and IL-13, and decreased the levels of IFN-g, deficient mice showed reduced Th2 cytokine production and bone IL-2, IL-12, and TNF-a (8, 11). marrow eosinophilia with parasitic helminth infection (17), and The differentiation of naive CD4+ T cells into Th2 cells is in- duced by APCs and also requires TCR-mediated signaling (19, 20). In vivo, gut dendritic cells and macrophages process vitamin *Laboratory of Molecular Cell Biology, Leidos Biomedical Research, Frederick A to generate RAs and present them to T cells during Ag pre- National Laboratory for Cancer Research, Frederick, MD 21702; and †Optical Mi- croscopy and Analysis Laboratory, Leidos Biomedical Research, Frederick National sentation and T cell activation (16, 21), indicating the important Laboratory for Cancer Research, Frederick, MD 21702 role of RAs in T cell activation and differentiation. Even though 1Current address: Graduate Center for Toxicology, Markey Cancer Center, University little is known about the mechanism of RAs’ regulation in this of Kentucky, Lexington, KY. process, their influence on T cell activation is suggested. T cell ORCID: 0000-0002-4502-233X (H.J.). activation markers CD69 and CD38 are upregulated by ATRA, Received for publication March 26, 2015. Accepted for publication November 17, indicating the engagement of RA-RAR signaling in T cell acti- 2015. vation (10). Moreover, RAs also upregulate transcriptional factors This work was supported in whole or in part by National Cancer Institute, National for Th2 differentiation, including cMAF, GATA-3, and STAT-6, Institutes of Health Contract HHSN261200800001E. This work was also supported by the National Institute of Allergy and Infectious Diseases. with a concomitant downregulation of the Th1 factor T-bet (11). All these observations indicate that RA-RAR signaling is engaged The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, com- in the induction of Th2 differentiation by RA. mercial products, or organizations imply endorsement by the U.S. Government. Leucine zipper transcription factor-like 1 (LZTFL1) was first Address correspondence and reprint requests to Dr. Ven Natarajan, Building 550/ identified as a tumor suppressor. The gene encoding LZTFL1 is Room 120, Leidos Biomedical Research, Frederick National Laboratory for Cancer located on human chromosome 3p21.3 and is found to be deleted in Research, Frederick, MD 21702. E-mail address: [email protected] several types of cancer (22). LZTFL1 overexpression in cervical The online version of this article contains supplemental material. cancer cell line HeLa cells inhibited anchorage-independent cell Abbreviations used in this article: ATRA, all-trans RA; BBS, Bardet–Biedl syn- drome; cSMAC, central supramolecular activation cluster; DIG, digoxigenin; DP, growth and cell migration in vitro and repressed tumor growth distal pole; IS, immunological synapse; LZTFL1, leucine-zipper transcription in vivo (23). Recently, a deletion mutant of LZTFL1 was also factor–like 1; RA, retinoic acid; RAR, RA receptor; SEE, staphylococcal entero- found in a family with Bardet–Biedl syndrome (BBS), which toxin E; siRNA, small interfering RNA. suggests that LZTFL1 is involved in BBS (24). Seo et al. (25) Copyright Ó 2016 by The American Association of Immunologists, Inc. 0022-1767/16/$30.00 further showed that LZTFL1 interacts with a BBS protein com- www.jimmunol.org/cgi/doi/10.4049/jimmunol.1500719 1082 T CELL ACTIVATION–INDUCED LZTFL1 ENHANCES IL-5 PRODUCTION plex, known as the BBSome, and regulates its primary ciliary CA) and the following primers: LZTFL1, forward, 59- GGCCTAAATGAG- trafficking. A role for LZTFL1 in hedgehog signaling is also CACCATCA-39 and reverse, 59-ATCCACTTCTCAGCTTGTGC-39; pre- suggested (24, 25). developed FAM- and TAMRA-labeled internal oligonucleotide probes and + primers for IL-5 and GAPDH (Life Technologies). The quantity of LZTFL1 In our effort to understand the role that ATRA plays in CD4 and IL-5 mRNAs was normalized by the levels of GAPDH mRNA. T cell development, we have found that both LZTFL1 mRNA and protein production are upregulated by ATRA treatment in human Western blot for LZTFL1 + + CD4 T cells. During CD4 T cell activation in contact with APC, Whole-cell proteins were extracted using M-PER mammalian protein LZTFL1 transiently localizes to the immunological synapse (IS). extraction reagent with protease inhibitor cocktails (Thermo Scientific, Overexpression of LZTFL1 in CD4+ T cells further enhanced the Waltham, MA). Protein extracts were electrophoresed in a 4–12% gradient NuPAGE Bis Tris Gel (Life Technologies), transferred to polyvinylidene T cell activation signal, as indicated by increased NFAT activity. difluoride membrane, and detected with fluorophore-labeled secondary Ab Moreover, LZTFL1 knockdown decreased Th2 cytokine produc-
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