Oestrogen-mediated protection of experimental autoimmune encephalomyelitis in the absence of Foxp3+ regulatory T cells implicates compensatory pathways including regulatory B cells

Sandhya Subramanian, Melissa Yates, Arthur A. Vandenbark, Halina Offner

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)340-347
Number of pages8
JournalImmunology
Volume132
Issue number3
DOIs
StatePublished - Mar 2011

Keywords

  • B cells
  • Experimental autoimmune encephalomyelitis
  • Foxp3
  • Foxp3-DTR
  • Oestrogen

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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