title: Treg suppressive activity involves estrogen-dependent expression of programmed death-1 (PD-1).
abstract: Estrogen [17-beta-estradiol (E2)] is a potent driver of the FoxP3+ regulatory T cell (Treg) compartment. Recently, Tregs were further characterized by intracellular expression of the negative co-stimulatory molecule, programmed death-1 (PD-1). To clarify the role of PD-1 versus FoxP3 in E2-enhanced Treg suppression, we evaluated both markers and functional suppression in wild-type, estrogen receptor knockout (ERKO) mice and PD-1 KO mice. We demonstrate that intracellular PD-1 expression is also E2 sensitive, since E2 treatment increased intracellular PD-1 levels in CD4+FoxP3+ cells, and PD-1 expression and Treg suppression were reduced in ERKO mice. Surprisingly, PD-1 KO mice retained normal levels of FoxP3 expression, but Tregs from these mice lacked functional suppression. However, E2 pre-treatment of PD-1 KO mice partially restored functional Treg suppression without enhancing FoxP3 expression. Thus, functional Treg suppression in immunized mice without E2 pre-treatment was more closely linked to PD-1 expression than to FoxP3 expression. However, although enhanced PD-1 expression was E2 dependent, functional suppression was still enhanced by E2 pre-treatment in the absence of PD-1. These data clearly demonstrate that E2 can affect multiple regulatory elements that influence Treg suppression, including both PD-1-dependent and PD-1-independent pathways.
authors.affiliation: Neuroimmunology Research, Veterans Affairs Medical Center, R&D-31, 3710 SW US Veterans Hospital Road, Portland, OR 97239, USA.
authors.forename: Magdalena J
authors.initials: MJ
authors.lastname: Polanczyk
authors.forename: Corwyn
authors.initials: C
authors.lastname: Hopke
authors.forename: Arthur A
authors.initials: AA
authors.lastname: Vandenbark
authors.forename: Halina
authors.initials: H
authors.lastname: Offner
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000378:metabolism; D000941:Antigens / Q000276:immunology; D000954:Antigens, Surface / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency* / Q000235:genetics; D002478:Cells, Cultured; D004958:Estradiol / Q000378:metabolism* / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000172:deficiency; D047629:Estrogen Receptor beta / Q000172:deficiency; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006023:Glycoproteins / Q000276:immunology; D007114:Immunization; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments / Q000276:immunology; D061026:Programmed Cell Death 1 Receptor; D011960:Receptors, Estrogen / Q000172:deficiency* / Q000187:drug effects / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*
chemical_list: D000941:Antigens; D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D006023:Glycoproteins; D063308:Myelin-Oligodendrocyte Glycoprotein; C491383:Pdcd1 protein, mouse; D010446:Peptide Fragments; D061026:Programmed Cell Death 1 Receptor; D011960:Receptors, Estrogen; C445081:myelin oligodendrocyte glycoprotein (35-55); D004958:Estradiol