Androgen Receptor (AR) ablation encumbers the expansion and function of T regulatory cells (Treg) in a male mouse model
Abstract
Background: Many autoimmune diseases have a higher prevalence in females than males but there is no clear explanation for this phenomenon. Naturally occurring CD4+CD25+FOXP3+ Treg cells carry out a vital role in immune tolerance. We postulate that androgen may influence Treg cells differentiation and function.
Methods: Eight to twelve weeks old wild-type (WT) and androgen receptor knockout (ARKO) male mice (C57BL/6) were utilized. Treg cells in diverse lymphoid organs were separated with an easySep selection kit and sorted with FACSAria. Treg cells were phenotypically and functionally characterized by flow cytometry analysis (FACS) and an in vitro immune suppressive assay.
Results: Significantly Lower prevalence of thymic and peripheral Treg cells were noted in ARKO mice compared to the WT mice. Sorted ARKO Treg cells were functionally less suppressive than their counterparts in WT mice.
Conclusion: Our data suggest that the androgen receptor (AR) signaling pathway may be implicated in Treg cell expansion and function. To our knowledge, this study is the first to look into how AR knockout affects Treg cells. Therefore, it might flashlight the mechanisms of inflammatory and autoimmune disease.
Keywords: Androgen receptor; ARKO mice; Immunity; Immunosuppression; Treg cells
Full Text:
PDFReferences
Walecki M, Eisel F, Klug J, Baal N, Paradowska-Dogan A, et al. Androgen receptor modulates Foxp3 expression in CD4+ CD25+ Foxp3+ regulatory T-cells. Molecular Biology of The Cell, (2015); 26(15): 2845-2857.
DeBoer MD, Phillips BR, Mauger DT, Zein J, Erzurum SC, et al. Effects of endogenous sex hormones on lung function and symptom control in adolescents with asthma. BMC Pulmonary Medicine, (2018); 18 (58): 1-10.
Zein JG, McManus JM, Sharifi N, Erzurum SC, Marozkina N, et al. Benefits of airway androgen receptor expression in human asthma. American Journal of Respiratory and Critical Care Medicine, (2021); 204(3): 285-293.
Conforti F, Pala L, Bagnardi V, De Pas T, Martinetti M, et al. Cancer immunotherapy efficacy and patients' sex: a systematic review and meta-analysis. The Lancet Oncology, (2018); 19(6): 737-746.
Abo-Aziza FAM, Zaki AA, Amer AS, Lotfy RA. Dihydrotestosterone and 17-Estradiol Enhancement of In Vitro Osteogenic Differentiation of Castrated Male Rat Bone Marrow Mesenchymal Stem Cells (rBMMSCs). International Journal of Hematology-Oncology and Stem Cell Research, (2019); 13(4): 208-219.
Dinesh R, Hahn B, Singh R; Sex hormones and gender influence the expression of Foxp3 and regulatory T cells in SLE patients. The Journal of Immunology, (2011); 186 (1_Supplement): 115-118.
Kamal M, Gabr H, Anwar S, Bastawy S, Salah L. The relation of CD4+ CD25+ Foxp3+ regulatory T cells concentration with disease activity and damage index in systemic lupus erythematosus. Lupus, (2022); 31(4): 463-471.
Fiyouzi T, Pelaez-Prestel HF, Reyes-Manzanas R, Lafuente EM, Reche PA. Enhancing regulatory T cells to treat inflammatory and autoimmune diseases. International Journal of Molecular Sciences, (2023); 24(9): 7797.
Giefing-Kröll C, Berger P, Lepperdinger G, Grubeck-Loebenstein B. How sex and age affect immune responses, susceptibility to infections, and response to vaccination. Aging Cell, (2015); 14(3): 309–321.
Polanczyk MJ, Carson BD, Subramanian S, Afentoulis M, Vandenbark AA, et al; Cutting edge: estrogen drives expansion of the CD4+CD25+ regulatory T cell compartment. Journal of Immunology, (2004); 173(40): 2227–2230.
Fijak M, Schneider E, Klug J, Bhushan S, Hackstein H, et al; Testosterone replacement effectively inhibits the development of experimental autoimmune orchitis in rats: evidence for a direct role of testosterone on regulatory T cell expansion. Journal of Immunology, (2011); 186(9): 5162–5172.
Marozkina N, Zein J, DeBoer MD, Logan L, Veri L, Ross K, et al; Dehydroepiandrosterone supplementation may benefit women with asthma who have low androgen levels: a pilot study. Pulmonary Therapy, (2019); 5: 213-20.
Page ST, Plymate SR, Bremner WJ, Matsumoto AM, Hess DL, et al; Effect of medical castration on CD4+ CD25+ T cells, CD8+ T cell IFN-γ expression, and NK cells: a physiological role for testosterone and/or its metabolites. American Journal of Physiology-Endocrinology and Metabolism, (2006); 290(5): E856-E863.
Braitch M, Harikrishnan S, Robins RA, Nichols C, Fahey AJ, et al. Glucocorticoids increase CD4+ CD25high cell percentage and Foxp3 expression in patients with multiple sclerosis. Acta Neurologica Scandinavica, (2009); 119(4): 239-245.
Bohács A, Cseh Á, Stenczer B, Müller V, Gálffy G, et al; Effector and regulatory lymphocytes in asthmatic pregnant women. American Journal of Reproductive Immunology, (2010); 64(6): 393-401.
Guan X, Polesso F, Wang C, Sehrawat A, Hawkins RM, et al. Androgen receptor activity in T cells limits checkpoint blockade efficacy. Natur, (2022); 606(7915): 791-796.
Zein J, Gaston B, Bazeley P, DeBoer MD, Igo Jr RP, et al. HSD3B1 genotype identifies glucocorticoid responsiveness in severe asthma. Proceedings of the National Academy of Sciences, (2020); 117(4): 2187-2193.
Gandhi VD, Cephus JY, Norlander AE, Chowdhury NU, Zhang J, et al. Androgen receptor signaling promotes Treg suppressive function during allergic airway inflammation. The Journal of Clinical Investigation, (2022); 132(4): 1-15.
Alawad A, Altuwaijri S, Aljarbu A, Kryczek I, Niu Y, et al. Depletion of androgen receptor (AR) in mesenchymal stem cells (MSCs) inhibits induction of CD4+ CD25+ FOX3+ regulatory T (Treg) cells via androgen TGF-β interaction. Journal of Applied Biomedicine, (2015); 13(4): 263-271.
Yeh S, Tsai MY, Xu Q, Mu XM, Lardy H, et al; Generation and characterization of androgen receptor knockout (ARKO) mice: an in vivo model for the study of androgen functions in selective tissues. Proceedings of the National Academy of Sciences, (2002); 99(21): 13498-13503.
Altuwaijri S, Chuang KH, Lai KP, Lai JJ, Lin HY, et al. Susceptibility to autoimmunity and B cell resistance to apoptosis in mice lacking androgen receptor in B cells. Molecular Endocrinology, (2009); 23(4): 444-453.
Duque A, Rakic P; Different effects of bromodeoxyuridine and [3H] thymidine incorporation into DNA on cell proliferation, position, and fate. Journal of Neuroscience, (2011); 31(42): 15205-15217.
Gray DH, Fletcher AL, Hammett M, Seach N, Ueno T, et al. Unbiased analysis, enrichment and purification of thymic stromal cells. Journal of immunological methods, (2008); 329(1-2): 56-66.
Kim R, Emi M, Tanabe K. Cancer immunosuppression and autoimmune disease: beyond immunosuppressive networks for tumour immunity. Immunology, (2006); 119(2): 254-264.
Rowe JH, Ertelt JM, Xin L, Way SS. Pregnancy imprints regulatory memory that sustains anergy to fetal antigen. Nature, (2012); 490(7418): 102-106.
Moulton VR. Sex hormones in acquired immunity and autoimmune disease. Frontiers in immunology, (2018); 9: 2279.
Klein SL, Flanagan KL. Sex differences in immune responses. Nature Reviews Immunology, (2016); 16: 626-638.
Shimba A, Ikuta K. Glucocorticoids regulate circadian rhythm of innate and adaptive immunity. Frontiers In Immunology, (2020); 11: 2143.
Wilhelmson AS, Lantero Rodriguez M, Johansson I, Svedlund Eriksson E, Stubelius A, et al. Androgen receptors in epithelial cells regulate thymopoiesis and recent thymic emigrants in male mice. Frontiers In Immunology, (2020); 11: 1342.
Ikuta K, Ejima A, Abe S, Shimba A. Control of immunity and allergy by steroid hormones. Allergology International, (2022); 71(4):432-436.
Dikiy S, Rudensky AY. Principles of regulatory T cell function. Immunity, (2023); 56(2): 240-255.
Eggenhuizen PJ, Ng BH, Ooi JD. Treg enhancing therapies to treat autoimmune diseases. International Journal of Molecular Sciences, (2020); 21(19): 7015.
Tough DF, Lombardi G. Therapeutic opportunities for regulatory T-cell enhancing approaches. Clinical and Experimental Immunology, (2023); 211(2): 93-95.
McCallion O, Bilici M, Hester J, Issa F. Regulatory T-cell therapy approaches. Clinical and Experimental Immunology, (2023); 211(2): 96-107.
Wan YY, Flavell RA. Identifying Foxp3-expressing suppressor T cells with a bicistronic reporter. Proceedings of the National Academy of Sciences, (2005); 102(14): 5126-5131.
Sakaguchi S. Naturally arising Foxp3-expressing CD25+ CD4+ regulatory T cells in immunological tolerance to self and non-self. Nature immunology, (2005); 6(4): 345-352.
Liva SM, Voskuhl RR. Testosterone acts directly on CD4+ T lymphocytes to increase IL-10 production. The Journal of Immunology, (2001); 167(4): 2060-2067.
Liu Z, Falo LD, You Z. Knockdown of HMGB1 in tumor cells attenuates their ability to induce regulatory T cells and uncovers naturally acquired CD8 T cell-dependent antitumor immunity. The Journal of Immunology, (2011); 187(1):118-125.
Shevyrev D, Tereshchenko V. Treg heterogeneity, function, and homeostasis. Frontiers In Immunology, (2020); 10: 3100.
Okeke EB, Uzonna JE. The pivotal role of regulatory T cells in the regulation of innate immune cells. Frontiers In Immunology, (2019); 10: 680.
Lee W, Lee GR. Transcriptional regulation and development of regulatory T cells. Experimental & molecular medicine, (2018); 50(3): e456- e456.
Schiavon V, Duchez S, Branchtein M, How-Kit A, Cassius C, et al. Microenvironment tailors nTreg structure and function. Proceedings of The National Academy of Sciences, (2019); 116(13): 6298-6307.
Malviya V, Yshii L, Junius S, Garg AD, Humblet‐Baron S, Schlenner SM. Regulatory T‐cell stability and functional plasticity in health and disease. Immunology and Cell Biology, (2023); 101(2): 112-29.
Amini L, Kaeda J, Fritsche E, Roemhild A, Kaiser D, Reinke P. Clinical adoptive regulatory T Cell therapy: State of the art, challenges, and prospective. Frontiers In Cell and Developmental Biology, (2023); 10: 1081644.
Baron KJ, Turnquist HR. Clinical Manufacturing of Regulatory T Cell Products For Adoptive Cell Therapy and Strategies to Improve Therapeutic Efficacy. Organogenesis, (2023); 19(1): 2164159.
Selck C, Dominguez-Villar M. Antigen-specific regulatory T cell therapy in autoimmune diseases and transplantation. Frontiers In Immunology, (2021); 12: 661875.
Abramson J, Anderson G. Thymic epithelial cells. Annual Review of Immunology, (2017); 35: 85-118.
Rodrigues PM, Ribeiro AR, Serafini N, Meireles C, Di Santo JP, Alves NL. Intrathymic deletion of IL-7 reveals a contribution of the bone marrow to thymic rebound induced by androgen blockade. The Journal of Immunology, (2018); 200(4):1389-98
Tang S, Dubey P. Opposing effects of androgen ablation on immune function in prostate cancer. Oncoimmunology, (2012); 1(7): 1220-1.
Samiea A, Yoon JS, Ong CJ, Zoubeidi A, Chamberlain TC, et al. Interleukin‐10 induces expression of neuroendocrine markers and PDL1 in prostate cancer cells. Prostate cancer, (2020); 2020(1): 5305306.
Hsu P, Santner-Nanan B, Hu M, Skarratt K, Lee CH, et al. IL-10 potentiates differentiation of human induced regulatory T cells via STAT3 and Foxo1. The Journal of Immunology, (2015); 195(8): 3665-3674.
Liu KS, Fan XQ, Zhang L, Wen QN, Feng JH, et al.; Effects of recombinant human interleukin‑10 on Treg cells, IL‑10 and TGF‑β in transplantation of rabbit skin. Molecular medicine reports, (2014); 9(2):639-644.
DOI: http://dx.doi.org/10.62940/als.v12i1.3275
Refbacks
- There are currently no refbacks.