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Calcitriol Regulates the Differentiation of IL-9–Secreting Th9 Cells by Modulating the Transcription Factor PU.1

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Calcitriol Regulates the Differentiation of IL-9–Secreting Th9 Cells by Modulating the Transcription Factor PU.1 Calcitriol Regulates the Differentiation of IL-9−Secreting Th9 Cells by Modulating the Transcription Factor PU.1 This information is current as Shachi Pranjal Vyas, Arman Kunwar Hansda, Mark H. of September 26, 2021. Kaplan and Ritobrata Goswami J Immunol published online 13 January 2020 http://www.jimmunol.org/content/early/2020/01/10/jimmun ol.1901205 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2020/01/10/jimmunol.190120 Material 5.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 26, 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 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 © 2020 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published January 13, 2020, doi:10.4049/jimmunol.1901205 The Journal of Immunology Calcitriol Regulates the Differentiation of IL-9–Secreting Th9 Cells by Modulating the Transcription Factor PU.1 Shachi Pranjal Vyas,* Arman Kunwar Hansda,* Mark H. Kaplan,† and Ritobrata Goswami* Vitamin D can modulate the innate and adaptive immune system. Vitamin D deficiency has been associated with various autoimmune diseases. Th9 cells are implicated in the pathogenesis of numerous autoimmune diseases. Thus, we investigated the role of calcitriol (active metabolite of vitamin D) in the regulation of Th9 cell differentiation. In this study, we have unraveled the molecular mechanisms of calcitriol-mediated regulation of Th9 cell differentiation. Calcitriol significantly diminished IL-9 secretion from murine Th9 cells associated with downregulated expression of the Th9-associated transcription factor, PU.1. Ectopic expression of VDR in Th9 cells attenuated the percentage of IL-9–secreting cells. VDR associated with PU.1 in Th9 cells. Using a series of mutations, we were able to dissect the VDR domain involved in the regulation of the Il9 gene. The VDR–PU.1 interaction prevented the accessibility of PU.1 to the Il9 gene promoter, thereby restricting its expression. However, the expression Downloaded from of Foxp3, regulatory T cell–specific transcription factor, was enhanced in the presence of calcitriol in Th9 cells. When Th9 cells are treated with both calcitriol and trichostatin A (histone deacetylase inhibitor), the level of IL-9 reached to the level of wild-type untreated Th9 cells. Calcitriol attenuated specific histone acetylation at the Il9 gene. In contrast, calcitriol enhanced the recruit- ment of the histone modifier HDAC1 at the Il9 gene promoter. In summary, we have identified that calcitriol blocked the access of PU.1 to the Il9 gene by reducing its expression and associating with it as well as regulated the chromatin of the Il9 gene to regulate expression. The Journal of Immunology, 2020, 204: 000–000. http://www.jimmunol.org/ he fat-soluble vitamin D plays crucial function in immune wide-range of immune cells, such as monocytes, macrophages, system regulation apart from its conventional function in NK cells, dendritic cells, B cells, and T cells, highlighting the T maintaining calcium and phosphorous homeostasis (1, 2). function of calcitriol in the immune system (2, 5). Active vitamin The biologically active form of vitamin D, designated as vitamin D promotes the antimicrobial mechanisms induced by macro- D3, or calcitriol, is a secosteroid hormone that is predominantly phages and neutrophils. Calcitriol prevents the maturation and synthesized in the skin from 7-dehydrocholesterol by UV-B rays differentiation of the dendritic cells and thereby impairs T cell (2). Calcitriol acts via vitamin D receptor (VDR), which belongs activation and differentiation, which, upon dysregulation, leads to the nuclear receptor superfamily (2, 3). Binding of calcitriol to the initiation and perpetuation of autoimmune diseases (2, 6, 7). by guest on September 26, 2021 brings about a change in conformation of VDR, followed by Globally, there has been increased prevalence of autoimmune dis- heterodimerization with an orphan receptor, retinoid X receptor eases, including rheumatoid arthritis, multiple sclerosis, Crohn (RXR). This heterodimer of VDR-RXR moves to the nucleus, disease, type 1 diabetes mellitus, and other immune-mediated dis- binds to the vitamin D response elements (VDRE) to regulate the eases (8). Vitamin D3 deficiency is associated with increased risk of transcription of more than 200 genes (2, 3). VDR is expressed by several autoimmune diseases (2, 4). Several studies suggest that numerous tissues, such as brain, breast, kidney, intestine, liver, and calcitriol supplementation attenuates the disease activity score and lung (4). Interestingly, VDR is also known to be expressed by a reduces disease exacerbation of various autoimmune diseases (9). Thus, a strong correlation between low vitamin D levels and the development of autoimmune diseases exists, and calcitriol supple- *School of Bioscience, Indian Institute of Technology Kharagpur, Kharagpur 721302, mentation might play a protective role in the pathophysiology of West Bengal, India; and †Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202 autoimmune diseases. ORCIDs: 0000-0002-2923-8245 (M.H.K.); 0000-0002-4388-7962 (R.G.). The principal immunological mechanism employed by calcitriol in providing protection against autoimmune diseases involves Received for publication October 3, 2019. Accepted for publication December 12, 2019. modulating the differentiation of various Th cell subsets (6, 7, 10). This work was supported by a Council of Scientific and Industrial Research– Increased frequencies of Th1 and Th17 cells are known to be University Grants Commission fellowship (to S.P.V.). A.K.H. acknowledges the responsible for the pathogenesis of multiple sclerosis, rheumatoid Ministry of Human Resource Development for providing a fellowship. R.G. was arthritis, and inflammatory bowel disease (11). Interestingly, cal- supported by the Young Scientist Scheme, Science and Engineering Research Board, Department of Science and Technology, Government of India (YSS/2015/001147). citriol treatment resulted in reduced frequency of pathogenic Th1 Address correspondence and reprint requests to Dr. Ritobrata Goswami, School of Bio- and Th17 cells in various autoimmune disease models and patients science, Indian Institute of Technology Kharagpur, Sir J.C. Bose Laboratory Complex, suffering from autoimmune diseases (10–12). This affirms the Kharagpur 721302, West Bengal, India. E-mail address: [email protected] protective role of calcitriol in autoimmune diseases via modulat- The online version of this article contains supplemental material. ing the development of pathogenic Th cells. In contrast, calcitriol Abbreviations used in this article: ChIP, chromatin immunoprecipitation; CNS, con- enhances the polarization of Th2 and regulatory T (Treg) cells. served noncoding sequence; DBD, DNA-binding domain; H3, histone 3; hCD4, human CD4; HEK, human embryonic kidney; Hr, hairless; LBD, ligand-binding The impact of calcitriol in the differentiation of IL-9–secreting domain; mVDR, murine VDR; qPCR, quantitative PCR; RXR, retinoid X receptor; Th9 cells is, however, not clearly understood. Th9 cells were Treg, regulatory T; TSA, trichostatin A; VDR, vitamin D receptor; VDRE, vitamin D discovered more than a decade ago and are known to impart response element. protection against helminth infections as well as exhibit antitumor Copyright Ó 2020 by The American Association of Immunologists, Inc. 0022-1767/20/$37.50 immune responses (13). Conversely, Th9 cells are also involved in www.jimmunol.org/cgi/doi/10.4049/jimmunol.1901205 2 CALCITRIOL-MEDIATED REGULATION OF Th9 CELLS the pathophysiology of several autoimmune diseases (14). Hence, Quantitative PCR and cytokine analysis modulating Th9 cell development might be an alternate strategy On day 5, differentiated Th cells were restimulated using anti-CD3 for for restraining the perpetuation and progression of autoimmune 6 h, and total mRNA was isolated by TRIzol (Thermo Fisher Scientific, diseases. Thus, owing to the pathological role of Th9 cells and the Waltham, MA). Reverse transcription of RNA into cDNA was performed protective effects of vitamin D supplementation in the patho- using the Verso cDNA Synthesis Kit and analyzed using PowerUp SYBR physiology of autoimmune diseases, we have investigated the role Green PCR Master Mix in QuantStudio 5 Real-Time PCR System (Thermo Fisher Scientific). The change in gene expression was normalized using and the molecular mechanisms employed by calcitriol in regu- b-actin as an endogenous control. The relative fold change in the gene lating Th9 cell development. expression was estimated using the equation 2(2DDCT). The primer se- In this study, we have observed that calcitriol attenuated the quences for real-time PCR have been depicted in the Supplemental Table I. secretion of IL-9 in murine Th9 cells associated with
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