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 Vandenbark, Halina Offner

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37 Citations (Scopus)

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

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Regulatory B-Lymphocytes
Autoimmune Experimental Encephalomyelitis
Regulatory T-Lymphocytes
Estrogens
T-Lymphocytes
Spleen
T-Cell Antigen Receptor Specificity
Peptide T
Diphtheria Toxin
Interleukin-13
Interleukin-17
Chemokine Receptors
Interleukin-10
Dendritic Cells
Interferons
Estradiol
B-Lymphocytes
Tumor Necrosis Factor-alpha
Lymph Nodes
Peptides

Keywords

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

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

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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.",
keywords = "B cells, Experimental autoimmune encephalomyelitis, Foxp3, Foxp3-DTR, Oestrogen",
author = "Sandhya Subramanian and Melissa Yates and Arthur Vandenbark and Halina Offner",
year = "2011",
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doi = "10.1111/j.1365-2567.2010.03380.x",
language = "English (US)",
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T1 - Oestrogen-mediated protection of experimental autoimmune encephalomyelitis in the absence of Foxp3+ regulatory T cells implicates compensatory pathways including regulatory B cells

AU - Subramanian, Sandhya

AU - Yates, Melissa

AU - Vandenbark, Arthur

AU - Offner, Halina

PY - 2011/3

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N2 - 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.

AB - 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.

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