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Bhlhe40 controls cytokine production by T cells and is essential for pathogenicity in autoimmune neuroinflammation.

Lin CC, Bradstreet TR, Schwarzkopf EA, Sim J, Carrero JA, Chou C, Cook LE, Egawa T, Taneja R, Murphy TL, Russell JH, Edelson BT - Nat Commun (2014)

Bottom Line: Bhlhe40 is required in vivo in a T cell-intrinsic manner, where it positively regulates the production of GM-CSF and negatively regulates the production of IL-10.In vitro, GM-CSF secretion is selectively abrogated in polarized Bhlhe40(-/-) TH1 and TH17 cells, and these cells show increased production of IL-10.These findings identify Bhlhe40 as a critical regulator of autoreactive T-cell pathogenicity.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA.

ABSTRACT
TH1 and TH17 cells mediate neuroinflammation in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. Pathogenic TH cells in EAE must produce the pro-inflammatory cytokine granulocyte-macrophage colony stimulating factor (GM-CSF). TH cell pathogenicity in EAE is also regulated by cell-intrinsic production of the immunosuppressive cytokine interleukin 10 (IL-10). Here we demonstrate that mice deficient for the basic helix-loop-helix (bHLH) transcription factor Bhlhe40 (Bhlhe40(-/-)) are resistant to the induction of EAE. Bhlhe40 is required in vivo in a T cell-intrinsic manner, where it positively regulates the production of GM-CSF and negatively regulates the production of IL-10. In vitro, GM-CSF secretion is selectively abrogated in polarized Bhlhe40(-/-) TH1 and TH17 cells, and these cells show increased production of IL-10. Blockade of IL-10 receptor in Bhlhe40(-/-) mice renders them susceptible to EAE. These findings identify Bhlhe40 as a critical regulator of autoreactive T-cell pathogenicity.

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IL-10R blockade renders Bhlhe40−/− mice susceptible to EAEa, Survival of WT or Bhlhe40−/− mice after EAE induction and biweekly treatment with control rat IgG or anti-IL-10R antibody. Data are combined from 3 independent experiments. b, Mean clinical scores of EAE in diseased WT or Bhlhe40−/− mice treated biweekly with either control rat IgG or anti-IL-10R antibody. Data are combined from 3 independent experiments. Error bars are not shown for clarity. All s.e.m. values were ≤1.
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Figure 6: IL-10R blockade renders Bhlhe40−/− mice susceptible to EAEa, Survival of WT or Bhlhe40−/− mice after EAE induction and biweekly treatment with control rat IgG or anti-IL-10R antibody. Data are combined from 3 independent experiments. b, Mean clinical scores of EAE in diseased WT or Bhlhe40−/− mice treated biweekly with either control rat IgG or anti-IL-10R antibody. Data are combined from 3 independent experiments. Error bars are not shown for clarity. All s.e.m. values were ≤1.

Mentions: We also tested whether blockade of IL-10 signaling could affect the development of EAE in Bhlhe40−/− mice. Groups of WT or Bhlhe40−/− mice were treated biweekly with control rat IgG or anti-IL-10R blocking antibody, beginning one day prior to immunization and continuing throughout the course of the experiment. Anti-IL-10R antibody treatment of immunized WT mice led to the high incidence of early morbidity and a shock-like syndrome, characterized by ruffled fur, weight loss, and a hunched posture, with rapid death prior to the onset of clinical EAE (Fig. 6a). This unexpected mortality, which we attribute to acute IL-10R blockade in the setting of a strong immune stimulus, was not apparent in immunized WT mice treated with control antibody, which experienced a typical course of EAE (Fig. 6b and Table 1). Immunized Bhlhe40−/− mice treated with anti-IL-10R antibody experienced only infrequent early morbidity. Those WT mice treated with anti-IL-10R antibody that did not succumb to an early death developed very severe EAE. Immunized Bhlhe40−/− mice treated with control antibody resisted EAE, while nearly half of all Bhlhe40−/− mice treated with anti-IL-10R antibody developed severe clinical EAE, like that of control antibody-treated WT mice. Overall, these results reveal that the pathogenicity of Bhlhe40−/− autoreactive T cells is regulated by IL-10.


Bhlhe40 controls cytokine production by T cells and is essential for pathogenicity in autoimmune neuroinflammation.

Lin CC, Bradstreet TR, Schwarzkopf EA, Sim J, Carrero JA, Chou C, Cook LE, Egawa T, Taneja R, Murphy TL, Russell JH, Edelson BT - Nat Commun (2014)

IL-10R blockade renders Bhlhe40−/− mice susceptible to EAEa, Survival of WT or Bhlhe40−/− mice after EAE induction and biweekly treatment with control rat IgG or anti-IL-10R antibody. Data are combined from 3 independent experiments. b, Mean clinical scores of EAE in diseased WT or Bhlhe40−/− mice treated biweekly with either control rat IgG or anti-IL-10R antibody. Data are combined from 3 independent experiments. Error bars are not shown for clarity. All s.e.m. values were ≤1.
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Figure 6: IL-10R blockade renders Bhlhe40−/− mice susceptible to EAEa, Survival of WT or Bhlhe40−/− mice after EAE induction and biweekly treatment with control rat IgG or anti-IL-10R antibody. Data are combined from 3 independent experiments. b, Mean clinical scores of EAE in diseased WT or Bhlhe40−/− mice treated biweekly with either control rat IgG or anti-IL-10R antibody. Data are combined from 3 independent experiments. Error bars are not shown for clarity. All s.e.m. values were ≤1.
Mentions: We also tested whether blockade of IL-10 signaling could affect the development of EAE in Bhlhe40−/− mice. Groups of WT or Bhlhe40−/− mice were treated biweekly with control rat IgG or anti-IL-10R blocking antibody, beginning one day prior to immunization and continuing throughout the course of the experiment. Anti-IL-10R antibody treatment of immunized WT mice led to the high incidence of early morbidity and a shock-like syndrome, characterized by ruffled fur, weight loss, and a hunched posture, with rapid death prior to the onset of clinical EAE (Fig. 6a). This unexpected mortality, which we attribute to acute IL-10R blockade in the setting of a strong immune stimulus, was not apparent in immunized WT mice treated with control antibody, which experienced a typical course of EAE (Fig. 6b and Table 1). Immunized Bhlhe40−/− mice treated with anti-IL-10R antibody experienced only infrequent early morbidity. Those WT mice treated with anti-IL-10R antibody that did not succumb to an early death developed very severe EAE. Immunized Bhlhe40−/− mice treated with control antibody resisted EAE, while nearly half of all Bhlhe40−/− mice treated with anti-IL-10R antibody developed severe clinical EAE, like that of control antibody-treated WT mice. Overall, these results reveal that the pathogenicity of Bhlhe40−/− autoreactive T cells is regulated by IL-10.

Bottom Line: Bhlhe40 is required in vivo in a T cell-intrinsic manner, where it positively regulates the production of GM-CSF and negatively regulates the production of IL-10.In vitro, GM-CSF secretion is selectively abrogated in polarized Bhlhe40(-/-) TH1 and TH17 cells, and these cells show increased production of IL-10.These findings identify Bhlhe40 as a critical regulator of autoreactive T-cell pathogenicity.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA.

ABSTRACT
TH1 and TH17 cells mediate neuroinflammation in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. Pathogenic TH cells in EAE must produce the pro-inflammatory cytokine granulocyte-macrophage colony stimulating factor (GM-CSF). TH cell pathogenicity in EAE is also regulated by cell-intrinsic production of the immunosuppressive cytokine interleukin 10 (IL-10). Here we demonstrate that mice deficient for the basic helix-loop-helix (bHLH) transcription factor Bhlhe40 (Bhlhe40(-/-)) are resistant to the induction of EAE. Bhlhe40 is required in vivo in a T cell-intrinsic manner, where it positively regulates the production of GM-CSF and negatively regulates the production of IL-10. In vitro, GM-CSF secretion is selectively abrogated in polarized Bhlhe40(-/-) TH1 and TH17 cells, and these cells show increased production of IL-10. Blockade of IL-10 receptor in Bhlhe40(-/-) mice renders them susceptible to EAE. These findings identify Bhlhe40 as a critical regulator of autoreactive T-cell pathogenicity.

Show MeSH
Related in: MedlinePlus