TY - JOUR
T1 - Treg suppressive activity involves estrogen-dependent expression of programmed death-1 (PD-1)
AU - Polanczyk, Magdalena J.
AU - Hopke, Corwyn
AU - Vandenbark, Arthur A.
AU - Offner, Halina
N1 - Funding Information:
The authors wish to thank Tasuku Honjo for providing PD-1 KO mice and Eva Niehaus for assistance in preparing and submitting the manuscript. This work was supported by grants NS23444, NS45445 and NS49210 from the National Institutes of Health, National Multiple Sclerosis Society grants RG3405A2, RG3400A4 and RG3794A4, The Nancy Davis MS Center Without Walls and the Biomedical Laboratory R&D Service, Department of Veterans Affairs.
PY - 2007/3
Y1 - 2007/3
N2 - Estrogen [17-β-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.
AB - Estrogen [17-β-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.
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U2 - 10.1093/intimm/dxl151
DO - 10.1093/intimm/dxl151
M3 - Article
C2 - 17267414
AN - SCOPUS:33847345997
SN - 0953-8178
VL - 19
SP - 337
EP - 343
JO - International Immunology
JF - International Immunology
IS - 3
ER -