title: Oestrogen-mediated protection of experimental autoimmune encephalomyelitis in the absence of Foxp3+ regulatory T cells implicates compensatory pathways including regulatory B cells.
abstract: Oestrogen (17β-oestradiol, E₂) is a highly effective treatment for experimental autoimmune encephalomyelitis (EAE) that may potentiate Foxp3+ regulatory T (Treg) cells, which in turn limit the expansion of encephalitogenic T-cell specificities. To determine if Treg cells constitute the major non-redundant protective pathway for E₂, we evaluated E₂ protection of EAE after targeted deletion of Foxp3 expression in Foxp3-DTR mice. Unexpectedly, E₂-treated Foxp3-deficient mice were completely protected against clinical and histological myelin oligodendrocyte glycoprotein (MOG)-35-55 peptide-induced EAE before succumbing to diphtheria toxin-induced mortality. This finding indicated the presence of alternative E₂-dependent EAE-protective pathways that could compensate for the lack of Treg cells. Further investigation revealed that E₂ treatment inhibited proliferation and expression of CCL2 and CXCL2, but enhanced secretion of interleukin-10 (IL-10) and IL-13 by MOG-35-55-specific spleen cells. These changes occurred concomitantly with increased expression of several chemokines and receptors, including CXCL13 and CXCR5, and the negative co-activation molecules, PD-L1 and B7.2, by B cells and dendritic cells. Furthermore, E₂ treatment resulted in higher percentages of spleen and lymph node T cells expressing IL-17, interferon-γ and tumour necrosis factor-α, but with lower expression of CCR6, suggesting sequestration of MOG-35-55 peptide-specific T cells in peripheral immune organs. Taken together, these data suggest that E₂-induced mechanisms that provide protection against EAE in the absence of Foxp3+ Treg cells include induction of regulatory B cells and peripheral sequestration of encephalitogenic T cells.
authors.affiliation: Neuroimmunology Research, Veterans' Affairs Medical Center, Portland, OR 97239, USA.
authors.forename: Sandhya
authors.initials: S
authors.lastname: Subramanian
authors.forename: Melissa
authors.initials: M
authors.lastname: Yates
authors.forename: Arthur A
authors.initials: AA
authors.lastname: Vandenbark
authors.forename: Halina
authors.initials: H
authors.lastname: Offner
mesh_terms: D000818:Animals; D016175:B-Lymphocyte Subsets / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects; D002469:Cell Separation; D016207:Cytokines / Q000096:biosynthesis / Q000187:drug effects; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D004958:Estradiol / Q000494:pharmacology*; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000276:immunology; D051379:Mice; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
chemical_list: D016207:Cytokines; D004967:Estrogens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D004958:Estradiol