Sex Hormones and Gender Influence the Expression of Markers of Regulatory T Cells in SLE Patients.

Publisher: Frontiers Research Foundation] Country of Publication: Switzerland NLM ID: 101560960 Publication Model: eCollection Cited Medium: Internet ISSN: 1664-3224 (Electronic) Linking ISSN: 16643224 NLM ISO Abbreviation: Front Immunol Subsets: MEDLINE

Original Publication: [Lausanne : Frontiers Research Foundation]

Biomarkers* ; Gene Expression Regulation*; Gonadal Steroid Hormones/*metabolism ; Lupus Erythematosus, Systemic/*etiology ; Lupus Erythematosus, Systemic/*metabolism ; T-Lymphocytes, Regulatory/*immunology ; T-Lymphocytes, Regulatory/*metabolism; Adult ; Aged ; Disease Susceptibility ; Female ; Gonadal Steroid Hormones/pharmacology ; Humans ; Immunophenotyping ; Leukocytes, Mononuclear/immunology ; Leukocytes, Mononuclear/metabolism ; Lupus Erythematosus, Systemic/pathology ; Male ; Middle Aged ; Sex Factors ; T-Lymphocyte Subsets/immunology ; T-Lymphocyte Subsets/metabolism ; Young Adult

Regulatory T cells have been implicated in the regulation and maintenance of immune homeostasis. Whether gender and sex hormones differentially influence the expression and function of regulatory T cell phenotype and their influence on FoxP3 expression remains obscure. We provide evidence in this study that the number and percent of human regulatory T cells (T regs ) expressing CD4 ⁺ and CD8 ⁺ are significantly reduced in healthy females compared to healthy males. In addition, both CD4 ⁺ CD25 ^+hi and CD8 ⁺ CD25 ^+hi subsets in healthy males have a 2-3 fold increase in FoxP3 mRNA expression compared to healthy females. Female SLE patients, compared to healthy women, have elevated plasma levels of estradiol and decreased levels of testosterone. Higher levels of testosterone correlate with higher expression of FoxP3 in CD4 ⁺ CD25 ^hi CD127 ^low putative T regs in women with SLE. Incubation of CD4 ⁺ regulatory T cells with 17β-estradiol at physiological levels generally decreased FoxP3 expression in females with SLE. These data suggest that females may be more susceptible than males to SLE and other autoimmune diseases in part because they have fewer T regs and reduced FoxP3 expression within those cells due to normal E2 levels which suppress FoxP3 expression. In addition, low levels of plasma testosterone in women may further reduce the ability of the T regs to express FoxP3. These data suggest that gender and sex hormones can influence susceptibility to SLE via effects on regulatory T cells and FoxP3 expression.
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2021 Singh and Bischoff.)

J Virol. 2014 May;88(9):4711-20. (PMID: 24522912)
Front Immunol. 2018 Mar 28;9:611. (PMID: 29643853)
Arthritis Rheumatol. 2016 Nov;68(11):2717-2727. (PMID: 27214349)
J Exp Med. 1994 Nov 1;180(5):1587-90. (PMID: 7964446)
J Biol Chem. 2015 Aug 14;290(33):20211-20. (PMID: 25987564)
Inflamm Bowel Dis. 2015 Jun;21(6):1409-18. (PMID: 25793328)
Drugs. 2014 Jul;74(11):1195-207. (PMID: 25022952)
J Rheumatol. 1987 Apr;14(2):268-72. (PMID: 3298648)
J Immunol. 2007 Jun 15;178(12):7649-57. (PMID: 17548601)
J Exp Med. 2016 Mar 7;213(3):377-97. (PMID: 26903244)
Eur J Clin Invest. 2007 Dec;37(12):987-96. (PMID: 18036033)
Int Immunol. 2004 Aug;16(8):1203-13. (PMID: 15237111)
J Immunol. 2004 May 1;172(9):5149-53. (PMID: 15100250)
Medicine (Baltimore). 1983 Sep;62(5):327-34. (PMID: 6225928)
Nat Immunol. 2003 Apr;4(4):337-42. (PMID: 12612581)
N Engl J Med. 2011 Dec 1;365(22):2110-21. (PMID: 22129255)
J Allergy Clin Immunol. 1999 Feb;103(2 Pt 1):282-8. (PMID: 9949320)
Science. 2003 Feb 14;299(5609):1057-61. (PMID: 12522256)
Immunol Lett. 2005 Feb 15;97(1):107-13. (PMID: 15626482)
Sci Signal. 2018 Apr 17;11(526):. (PMID: 29666308)
Clin Immunol. 2008 May;127(2):151-7. (PMID: 18299252)
Semin Immunol. 2011 Dec;23(6):438-45. (PMID: 21893418)
Arthritis Rheum. 1987 Mar;30(3):241-8. (PMID: 3032210)
J Clin Invest. 2003 Jan;111(2):275-83. (PMID: 12531884)
J Immunol. 2005 Dec 15;175(12):8392-400. (PMID: 16339581)
J Immunol. 2008 Feb 15;180(4):2069-80. (PMID: 18250412)
J Genet. 2013 Apr;92(1):163-71. (PMID: 23640423)
J Rheumatol. 2006 Jun;33(6):1093-101. (PMID: 16755656)
Arthritis Rheum. 1999 Feb;42(2):328-37. (PMID: 10025928)
Ann Rheum Dis. 2010 Jan;69 Suppl 1:i65-66. (PMID: 19995748)
Cell. 1996 May 3;85(3):303-6. (PMID: 8616885)
J Immunol. 2005 Feb 1;174(3):1446-55. (PMID: 15661903)
J Immunol. 2004 Aug 15;173(4):2227-30. (PMID: 15294932)
J Clin Invest. 2017 Mar 1;127(3):772-779. (PMID: 28248202)
Cell Immunol. 2015 Apr;294(2):70-9. (PMID: 25619140)
Immunology. 2006 Feb;117(2):280-6. (PMID: 16423064)
Int Immunol. 2004 Nov;16(11):1643-56. (PMID: 15466453)
Arthritis Rheum. 1992 Jun;35(6):630-40. (PMID: 1599520)
Semin Immunol. 2011 Jun;23(3):202-8. (PMID: 21840222)
Lupus. 2011 Feb;20(2):137-43. (PMID: 21078762)
Am J Transplant. 2004 Oct;4(10):1614-27. (PMID: 15367216)
Front Immunol. 2018 Oct 04;9:2279. (PMID: 30337927)
Am J Physiol Endocrinol Metab. 2006 May;290(5):E856-63. (PMID: 16352669)
Front Immunol. 2018 Apr 17;9:794. (PMID: 29755457)
Environ Health Perspect. 1999 Oct;107 Suppl 5:681-6. (PMID: 10502531)
J Autoimmun. 2010 Nov;35(3):269-75. (PMID: 20638240)
Int Immunol. 2017 Aug 1;29(8):365-375. (PMID: 29048538)
J Immunol. 2004 Sep 1;173(5):3542-8. (PMID: 15322219)
Nat Immunol. 2003 Apr;4(4):330-6. (PMID: 12612578)
Clin Immunol Immunopathol. 1998 Nov;89(2):171-80. (PMID: 9787119)
Arthritis Rheum. 2004 Sep;50(9):2858-68. (PMID: 15452837)
Proc Natl Acad Sci U S A. 2004 Mar 30;101(13):4572-7. (PMID: 15070759)
J Immunol. 2011 Sep 1;187(5):2386-93. (PMID: 21810607)
Front Immunol. 2019 Apr 09;10:680. (PMID: 31024539)
Front Immunol. 2015 Sep 28;6:493. (PMID: 26441996)
Nat Genet. 2001 Jan;27(1):68-73. (PMID: 11138001)
Immunology. 2015 Jun;145(2):232-41. (PMID: 25581706)
Mol Immunol. 2013 Dec;56(4):328-39. (PMID: 23911387)
Cell. 2008 May 30;133(5):775-87. (PMID: 18510923)
Ann Rheum Dis. 2010 Sep;69(9):1603-11. (PMID: 20699243)
Arthritis Rheum. 2007 Jun;56(6):1910-20. (PMID: 17530636)
J Immunol. 1998 Feb 1;160(3):1212-8. (PMID: 9570536)
Nat Med. 2015 Jun;21(6):638-46. (PMID: 26005855)
Arthritis Rheum. 1982 Jul;25(7):843-6. (PMID: 7104055)
J Immunol. 2005 Dec 1;175(11):7728-37. (PMID: 16301683)
J Immunol. 2007 Feb 15;178(4):2579-88. (PMID: 17277168)
Arthritis Rheumatol. 2014 Oct;66(10):2849-61. (PMID: 24942956)
Scand J Immunol. 2004 Feb;59(2):198-202. (PMID: 14871297)
Adv Exp Med Biol. 2007;601:113-9. (PMID: 17712998)
J Immunol. 2009 Feb 1;182(3):1689-95. (PMID: 19155519)
Ann Rheum Dis. 2008 May;67(5):664-71. (PMID: 17728327)
Postepy Dermatol Alergol. 2017 Dec;34(6):517-525. (PMID: 29422815)
J Immunol. 2004 Feb 1;172(3):1531-9. (PMID: 14734731)
Int Immunol. 2008 Jul;20(7):861-8. (PMID: 18469329)
J Immunol. 2006 Mar 1;176(5):2703-10. (PMID: 16493025)
J Immunol. 2016 May 1;196(9):3631-41. (PMID: 27001954)
J Clin Invest. 2000 Dec;106(12):R75-81. (PMID: 11120765)
Arch Intern Med. 1982 Oct;142(10):1813-5. (PMID: 7125767)
Immunity. 2000 Apr;12(4):431-40. (PMID: 10795741)
Arthritis Rheum. 1997 Sep;40(9):1725. (PMID: 9324032)
Nat Med. 2013 Jun;19(6):739-46. (PMID: 23624599)
Nat Immunol. 2001 Sep;2(9):777-80. (PMID: 11526384)
Science. 1994 Aug 26;265(5176):1237-40. (PMID: 7520605)
J Biol Chem. 2013 Aug 23;288(34):24494-502. (PMID: 23853094)
Arthritis Rheum. 1982 Nov;25(11):1271-7. (PMID: 7138600)
Clin Immunol. 2000 May;95(2):124-34. (PMID: 10779406)
Immunol Rev. 2005 Apr;204:195-207. (PMID: 15790360)
J Autoimmun. 2003 Nov;21(3):273-6. (PMID: 14599852)
Nat Immunol. 2018 Feb;19(2):108-119. (PMID: 29348500)
Arthritis Rheum. 2003 Aug;48(8):2100-10. (PMID: 12905462)
Mediators Inflamm. 2018 Dec 23;2018:4316584. (PMID: 30670926)
Clin Exp Immunol. 2008 Jul;153(1):44-55. (PMID: 18505436)
J Immunol. 2011 May 1;186(9):5162-72. (PMID: 21441459)
Front Biosci. 2001 Dec 01;6:E193-206. (PMID: 11724682)
J Exp Med. 2003 Dec 15;198(12):1875-86. (PMID: 14676299)
Nat Rev Immunol. 2002 Jan;2(1):46-53. (PMID: 11905837)
J Immunol. 1995 Aug 1;155(3):1151-64. (PMID: 7636184)
Front Neuroendocrinol. 2014 Aug;35(3):347-69. (PMID: 24793874)
Best Pract Res Clin Rheumatol. 2017 Jun;31(3):306-320. (PMID: 29224673)
Autoimmun Rev. 2010 Jun;9(8):560-8. (PMID: 20385256)
Annu Rev Immunol. 2006;24:209-26. (PMID: 16551248)
Arthritis Res Ther. 2008;10(6):227. (PMID: 19040771)
Rheum Dis Clin North Am. 2014 Aug;40(3):401-12, vii. (PMID: 25034153)
J Cell Physiol. 2008 Feb;214(2):456-64. (PMID: 17654501)
Clin Sci (Lond). 2016 Aug 1;130(16):1453-67. (PMID: 27231253)
Mol Biol Cell. 2015 Aug 1;26(15):2845-57. (PMID: 26063731)
Int Immunol. 2008 Jul;20(7):937-47. (PMID: 18495626)
FEBS Lett. 1998 Feb 6;422(3):349-53. (PMID: 9498814)
Annu Rev Immunol. 2004;22:531-62. (PMID: 15032588)
J Immunol. 2007 Feb 15;178(4):2572-8. (PMID: 17277167)

Keywords: 17β-estradiol; gender; regulatory T cells; sex hormones; systemic lupus erythematosus

0 (Biomarkers)
0 (Gonadal Steroid Hormones)

Date Created: 20210322 Date Completed: 20210628 Latest Revision: 20210628

20231215

PMC7966510

10.3389/fimmu.2021.619268

33746959