Estradiol enhances primary antigen-specific CD4 T cell responses and Th1 development in vivo. Essential role of estrogen receptor alpha expression in hematopoietic cells.
It is widely accepted that females have superior immune responses than males, but the ways by which sex hormones may enhance T cell responses are still poorly understood. In the present study, we analyzed the effect of estrogens on CD4 T cell activation and differentiation after immunization with exogenous antigens. We show that administration of low doses of 17beta-estradiol (E2) to castrated female mice results in a striking increase of antigen-specific CD4 T cell responses and in the selective development of IFN-gamma-producing cells. Quantitative assessment of the frequency of T cells bearing a public TCR beta chain CDR3 motif demonstrated that the clonal size of primary antigen-specific CD4 T cells was dramatically increased in immune lymph nodes from E2-treated mice. By using mice with disrupted estrogen receptor (ER) alpha or beta genes, we show that ERalpha, but not ERbeta, was necessary for the enhanced E2-driven Th1 cell responsiveness. Furthermore, ERalpha expression in hematopoietic cells was essential, since E2 effects on Th1 responses were only observed in mice reconstituted with bone marrow cells from ERalpha+/+, but not ERalpha-deficient mice. These results demonstrate that estrogen administration promotes strong antigen-specific Th1 cell responses in a mechanism that requires functional expression of ERalpha in hematopoietic cells.
Maret
Arlette
A
INSERM U397, Institut Louis Bugnard, CHU Rangueil, Toulouse, France.
Coudert
Jérôme D
JD
Garidou
Lucile
L
Foucras
Gilles
G
Gourdy
Pierre
P
Krust
Andrée
A
Dupont
Sonia
S
Chambon
Pierre
P
Druet
Philippe
P
Bayard
Francis
F
Guéry
Jean-Charles
JC
D020816:Amino Acid Motifs; D000818:Animals; D016026:Bone Marrow Transplantation; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D005260:Female; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; D018390:Gene Targeting; D006412:Hematopoietic Stem Cells / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D008198:Lymph Nodes / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010052:Ovariectomy; D011828:Radiation Chimera; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology; D011960:Receptors, Estrogen / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013047:Specific Pathogen-Free Organisms; D018417:Th1 Cells / Q000166:cytology / Q000187:drug effects*
D004268:DNA-Binding Proteins; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; C499308:Rag2 protein, mouse; D016693:Receptors, Antigen, T-Cell, alpha-beta; D011960:Receptors, Estrogen; C064655:V(D)J recombination activating protein 2; D015847:Interleukin-4; D004958:Estradiol; D007371:Interferon-gamma