International Immunology Advance Access originally published online on January 30, 2007
International Immunology 2007 19(3):337-343; doi:10.1093/intimm/dxl151
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Treg suppressive activity involves estrogen-dependent expression of programmed death-1 (PD-1)
1 Neuroimmunology Research, Veterans Affairs Medical Center, R&D-31, 3710 SW US Veterans Hospital Road, Portland, OR 97239, USA
2 Department of Neurology, Oregon Health and Science University, Portland, OR 97239, USA
3 Department of Food Hygiene, Faculty of Veterinary Medicine, Warsaw Agricultural University, Warsaw, Poland
4 Department of Molecular Microbiology and Immunology
5 Department of Anesthesiology and Perioperative Medicine, Oregon Health and Science University, Portland, OR 97239, USA
Correspondence to: H. Offner; E-mail: offnerva{at}ohsu.edu
Estrogen [17-ß-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.
Keywords: autoimmunity, co-stimulation, EAE/MS, T cells, tolerance/suppression
Transmitting editor: L. Steinman
Received 3 November 2006, accepted 27 December 2006.
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