An Inconvenient Variable: Sex Hormones and Their Impact on T Cell Responses Melissa A. Brown and Maureen A. Su This information is current as J Immunol 2019; 202:1927-1933; ; of September 26, 2021. doi: 10.4049/jimmunol.1801403 http://www.jimmunol.org/content/202/7/1927 Downloaded from References This article cites 71 articles, 26 of which you can access for free at: http://www.jimmunol.org/content/202/7/1927.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • 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 by guest on September 26, 2021 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 © 2019 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. An Inconvenient Variable: Sex Hormones and Their Impact on T Cell Responses Melissa A. Brown* and Maureen A. Su†,‡ Epidemiologic data demonstrate sex differences in au- by female congressional representatives and scientists, that the toimmune diseases, immune responses against infec- National Institutes of Health announced a policy to ensure that tion, and antitumor immunity, and accumulating sex is considered as a biological variable and that all National evidence suggests a major role for sex hormones in me- Institutes of Health–funded preclinical studies would include diating these differences. In this study, we review recent both males and females. This policy has resulted in a wealth advances in understanding how sex hormones regulate of new data, and we are beginning to uncover the underlying T cell responses to alter susceptibility to autoimmunity. immune mechanisms that dictate these differences. In this Although sex hormones can directly alter gene tran- study, we provide a brief overview of recent advances in our Downloaded from scriptional programs of T cells, we focus in this study understanding of sex-dependent immune responses with a fo- on how sex hormones alter T cell development and cus on how sex hormones differentially regulate T lymphocytes function through their effects on thymic stromal cells to alter susceptibility to disease. and innate cell types. In addition to contributing to Sex hormones and their receptors our understanding of sex differences, these findings also http://www.jimmunol.org/ have implications for the therapeutic use of sex hor- Estrogens, progesterone, and androgens are the major gonadal mones and sex hormone modulators, which are now being sex hormones (reviewed in Ref. 6). Estrogens include estrone, prescribed to increasing numbersofpatientsforawide 17b-estradiol, and estriol and are derived from aromatization variety of indications. The Journal of Immunology, of androgens by a single aromatase (P450aro) enzyme. P450aro is expressed in steroidogenic tissue (ovarian gran- 2019, 202: 1927–1933. ulosa cells in premenopausal women as well as the placenta during pregnancy) and in nonglandular tissue (fat and bone). ex differences, defined by distinct chromosome con- Progesterone is also produced by ovarian granulosa cells, the tent, unique reproductive organs, and sex-determined adrenal glands, the corpus luteum during the menstrual cycle, by guest on September 26, 2021 S steroid hormone levels, dictate many aspects of our and the placenta. The major sources of androgens are the testes being. It is now well-documented that our immune responses and adrenal glands. Leydig cells of the testes are the major are critically determined by sex, as illustrated by the pre- source of testosterone in males, and zona reticularis of the ad- dominance of females with multiple autoimmune diseases renal gland produces dehydroepiandrosterone sulfate in males in which female to male ratios can approach 11:1 (1). Sex and females. Testosterone is converted to dihydrotestosterone, a dimorphism in antitumor immunity and responses to more biologically active form of testosterone, by 5a-reductase in infection/vaccination are also apparent (reviewed in Ref. 2). testosterone target tissues (scalp and other peripheral tissues and For instance, in a recent study of men and women receiving male reproductive tissues). trivalent-inactivated seasonal influenza vaccine, increased The classical sex hormone receptors, the estrogen receptors proinflammatory cytokines and Ab responses were seen in (ER) ERa and ERb, the progesterone receptor (PR) isoforms females (3). Yet, despite the preponderance of evidence, PRA and PRB, and the androgen receptor (AR), function as disease-related studies have historically ignored the contri- hormone-activated transcription factors that bind to hor- bution of sex (4). Males or male-derived cells have routinely mone response elements in target genes to elicit gene ex- been used to study many aspects of human health, and until the pression (reviewed in Ref. 7). As such, sex hormone/receptor 1990s, females of childbearing age were excluded from drug complexes can regulate transcription through direct inter- trials (5). It was not until 2015, after much lobbying, primarily actions with specific DNA sequences. Known as hormone *Department of Microbiology and Immunology, Feinberg School of Medicine, NS079683 and R01 NS107851, the APS1 Foundation, and the Parker Institute for Northwestern University, Chicago, IL 60611; †Department of Microbiology, Im- Cancer Immunotherapy (all to M.A.S.). munology and Molecular Genetics, David Geffen School of Medicine, College of Address correspondence and reprint requests to Dr. Maureen A. Su, University of Life Sciences, University of California at Los Angeles, Los Angeles, CA 90095; and California at Los Angeles, Biomedical Sciences Research Building, 615 Charles E. Young ‡Department of Pediatrics, David Geffen School of Medicine, University of California Drive East, Los Angeles, CA 90095. E-mail address: [email protected] at Los Angeles, Los Angeles, CA 90095 Abbreviations used in this article: AIRE, autoimmune regulator; AR, androgen receptor; ORCID: 0000-0002-3680-9982 (M.A.S.). cTEC, cortical thymic epithelial cell; Dll, d-like; EAE, experimental autoimmune en- Received for publication October 17, 2018. Accepted for publication December 5, 2018. cephalomyelitis; ER, estrogen receptor; ILC, innate lymphoid cell; MS, multiple sclero- sis; mTEC, medullary thymic epithelial cell; PR, progesterone receptor; SLE, systemic This work was supported by National Institutes of Health (NIH), National Multiple lupus erythematosus; Treg, regulatory T cell; TSA, tissue self-antigen. Sclerosis Society Grants RG 4684A5/1 and RG 5281-A-3, and NIH Grants R21 NS081598 and RO1AI12829 (all to M.A.B.) as well as NIH Grants R01 Copyright Ó 2019 by The American Association of Immunologists, Inc. 0022-1767/19/$37.50 www.jimmunol.org/cgi/doi/10.4049/jimmunol.1801403 1928 BRIEF REVIEWS: SEX HORMONES AND T CELL RESPONSES response elements, these sequences have been identified at promoters of several genes with critical roles in immune responses. For instance, the IFN-g promoter possesses four putative estrogen response elements, and 17b-estradiol drives the expression of promoter–reporter constructs in transiently transfected lymphoid cells (8). This finding suggests the possibility that higher estrogen levels in females drive in- creased T cell IFN-g production and, in this way, predispose females to IFN-g2mediated autoimmune conditions. At the same time, androgen/AR action in CD4+ T cells may also prevent autoimmunity in males by directly increasing ex- pression of Ptpn1, a,phosphatase that inhibits Th1 differen- tiation (9). Androgen/AR complexes can also directly induce anti-inflammatory IL-10 expression by CD4+ T cells, which has been proposed to underlie male protection from CNS autoimmunity (10). These findings suggest that sex differ- ences in autoimmunity may be attributed to direct alteration of T cell transcriptional profiles by sex hormones. Downloaded from It is now clear, however, that this paradigm is overly sim- FIGURE 1. Sex hormone effects on thymus cell types. Sex hormones plistic. First, sex hormone–receptor interactions can exert their induce apoptosis of double-positive (DP) progenitors. Additionally, sex effects through DNA-independent mechanisms, such as the hormones directly modulate gene expression in thymic epithelial cells. activation of cytoplasmic signal transduction pathways (11). Androgens downregulate Dll expression in cTECs to inhibit thymopoiesis GPER1, for example, is a G protein–coupled ER localized while upregulating Aire in mTECs to promote negative selection of self- reactive T cells. Estrogen downregulates Aire in mTECs to inhibit thy- to the cell membrane that elicits the activation of a variety mocyte negative selection. http://www.jimmunol.org/ of cytoplasmic signaling molecules, including ERK/MAPK, PKC, PI3K and cAMP (12). Moreover, ERa can also exert its effects through cytoplasmic signaling (13), and activation of In the thymus, androgens can directly mediate apoptosis of nontranscriptional signaling mechanisms have also