Treg suppressive activity involves estrogen-dependent expression of programmed death-1 (PD-1)

Int Immunol. 2007 Mar;19(3):337-43. doi: 10.1093/intimm/dxl151. Epub 2007 Jan 30.


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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antigen-Presenting Cells / metabolism
  • Antigens / immunology
  • Antigens, Surface / genetics
  • Apoptosis Regulatory Proteins / deficiency*
  • Apoptosis Regulatory Proteins / genetics
  • Cells, Cultured
  • Estradiol / metabolism*
  • Estradiol / pharmacology
  • Estrogen Receptor alpha / deficiency
  • Estrogen Receptor beta / deficiency
  • Female
  • Forkhead Transcription Factors / metabolism*
  • Glycoproteins / immunology
  • Immunization
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myelin-Oligodendrocyte Glycoprotein
  • Peptide Fragments / immunology
  • Programmed Cell Death 1 Receptor
  • Receptors, Estrogen / deficiency*
  • Receptors, Estrogen / drug effects
  • Receptors, Estrogen / genetics
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / metabolism*


  • Antigens
  • Antigens, Surface
  • Apoptosis Regulatory Proteins
  • Estrogen Receptor alpha
  • Estrogen Receptor beta
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Glycoproteins
  • Myelin-Oligodendrocyte Glycoprotein
  • Pdcd1 protein, mouse
  • Peptide Fragments
  • Programmed Cell Death 1 Receptor
  • Receptors, Estrogen
  • myelin oligodendrocyte glycoprotein (35-55)
  • Estradiol