title: Estrogen receptor α signaling in T lymphocytes is required for estradiol-mediated inhibition of Th1 and Th17 cell differentiation and protection against experimental autoimmune encephalomyelitis.
abstract: Estrogen treatment exerts a protective effect on experimental autoimmune encephalomyelitis (EAE) and is under clinical trial for multiple sclerosis therapy. Estrogens have been suspected to protect from CNS autoimmunity through their capacity to exert anti-inflammatory as well as neuroprotective effects. Despite the obvious impacts of estrogens on the pathophysiology of multiple sclerosis and EAE, the dominant cellular target that orchestrates the anti-inflammatory effect of 17β-estradiol (E2) in EAE is still ill defined. Using conditional estrogen receptor (ER) α-deficient mice and bone marrow chimera experiments, we show that expression of ERα is critical in hematopoietic cells but not in endothelial ones to mediate the E2 inhibitory effect on Th1 and Th17 cell priming, resulting in EAE protection. Furthermore, using newly created cell type-specific ERα-deficient mice, we demonstrate that ERα is required in T lymphocytes, but neither in macrophages nor dendritic cells, for E2-mediated inhibition of Th1/Th17 cell differentiation and protection from EAE. Lastly, in absence of ERα in host nonhematopoietic tissues, we further show that ERα signaling in T cells is necessary and sufficient to mediate the inhibitory effect of E2 on EAE development. These data uncover T lymphocytes as a major and nonredundant cellular target responsible for the anti-inflammatory effects of E2 in Th17 cell-driven CNS autoimmunity.
authors.affiliation: INSERM, U1043, Toulouse F-31300, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Lélu
authors.forename: Sophie
authors.initials: S
authors.lastname: Laffont
authors.forename: Laurent
authors.initials: L
authors.lastname: Delpy
authors.forename: Pierre-Emmanuel
authors.initials: PE
authors.lastname: Paulet
authors.forename: Therese
authors.initials: T
authors.lastname: Périnat
authors.forename: Stefan A
authors.initials: SA
authors.lastname: Tschanz
authors.forename: Lucette
authors.initials: L
authors.lastname: Pelletier
authors.forename: Britta
authors.initials: B
authors.lastname: Engelhardt
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Guéry
mesh_terms: D000818:Animals; D015139:Blotting, Southern; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002469:Cell Separation; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000276:immunology / Q000378:metabolism*; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D005434:Flow Cytometry; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D018417:Th1 Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D058504:Th17 Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology
chemical_list: D047628:Estrogen Receptor alpha; D004967:Estrogens; D004958:Estradiol