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Interferon-β suppresses murine Th1 cell function in the absence of antigen-presenting cells.

Boivin N, Baillargeon J, Doss PM, Roy AP, Rangachari M - PLoS ONE (2015)

Bottom Line: CD4+ T cells express the type I interferon receptor, and IFN-β can suppress Th1 cell proliferation under APC-free stimulation conditions.Further, IFN-β treatment of Th1 cells upregulates phosphorylation of Stat1, and downregulates phosphorylation of Stat4.Our data indicate that IFN-γ-producing Th1 cells are directly responsive to IFN-β and point to a novel mechanism of IFN-β-mediated T cell suppression that is independent of APC-derived signals.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, Centre de recherche du CHU de Québec-Université Laval, Québec QC, Canada G1V 4G2.

ABSTRACT
Interferon (IFN)-β is a front-line therapy for the treatment of the relapsing-remitting form of multiple sclerosis. However, its immunosuppressive mechanism of function remains incompletely understood. While it has been proposed that IFN-β suppresses the function of inflammatory myelin antigen-reactive T cells by promoting the release of immunomodulatory cytokines such as IL-27 from antigen-presenting cells (APCs), its direct effects on inflammatory CD4+ Th1 cells are less clear. Here, we establish that IFN-β inhibits mouse IFN-γ+ Th1 cell function in the absence of APCs. CD4+ T cells express the type I interferon receptor, and IFN-β can suppress Th1 cell proliferation under APC-free stimulation conditions. IFN-β-treated myelin antigen-specific Th1 cells are impaired in their ability to induce severe experimental autoimmune encephalomyelitis (EAE) upon transfer to lymphocyte-deficient Rag1-/- mice. Polarized Th1 cells downregulate IFN-γ and IL-2, and upregulate the negative regulatory receptor Tim-3, when treated with IFN-β in the absence of APCs. Further, IFN-β treatment of Th1 cells upregulates phosphorylation of Stat1, and downregulates phosphorylation of Stat4. Our data indicate that IFN-γ-producing Th1 cells are directly responsive to IFN-β and point to a novel mechanism of IFN-β-mediated T cell suppression that is independent of APC-derived signals.

No MeSH data available.


Related in: MedlinePlus

IFN-β regulates Stat1 and Stat4 expression on Th cells in the absence of APCs.CD4+CD62LhiCD25- T cells were sorted from the spleens and lymph nodes of C57BL6/J mice. They were stimulated with plate-bound anti-CD3+anti-CD28 under Th1 or Th17 conditions, with the indicated concentrations of IFN-β, for 48 hours, and cell lysates were generated. A. Expression of Stat1 and pStat1(Y701) were assessed by Western blot. Representative of two experiments. B. Expression of Stat4 and pStat4(Y693) were assessed by Western blot. Representative of three experiments. GAPDH, loading control.
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pone.0124802.g005: IFN-β regulates Stat1 and Stat4 expression on Th cells in the absence of APCs.CD4+CD62LhiCD25- T cells were sorted from the spleens and lymph nodes of C57BL6/J mice. They were stimulated with plate-bound anti-CD3+anti-CD28 under Th1 or Th17 conditions, with the indicated concentrations of IFN-β, for 48 hours, and cell lysates were generated. A. Expression of Stat1 and pStat1(Y701) were assessed by Western blot. Representative of two experiments. B. Expression of Stat4 and pStat4(Y693) were assessed by Western blot. Representative of three experiments. GAPDH, loading control.

Mentions: Stat1 and Stat4 are transcription factors that are crucial to initial steps in Th1 cell differentiation. Stat1 is phosphorylated upon T cell exposure to IFN-γ, while Stat4 activity is induced by IL-12 [42]. As our data indicate that IFN-β can modulate Th1 cell function in vitro and in vivo, we wanted to examine its effects on Stat1 and Stat4 activity in Th1 cells. To our surprise, we found that IFN-β strongly induced Stat1 phosphorylation at tyrosine residue 701 (Y701) in Th1 and Th17 cells. (Fig 5A). It was previously demonstrated that Th17 differentiation conditions can induce Stat1 [43]. By contrast, phosphorylation of Stat4 at Y693 in Th1 cells was markedly reduced by IFN-β (Fig 5B). These data suggest that while IFN-β can enhance sensitivity of Th1 cells to IFN-γ, it downmodulates their response to the key Th1 differentiation cytokine IL-12.


Interferon-β suppresses murine Th1 cell function in the absence of antigen-presenting cells.

Boivin N, Baillargeon J, Doss PM, Roy AP, Rangachari M - PLoS ONE (2015)

IFN-β regulates Stat1 and Stat4 expression on Th cells in the absence of APCs.CD4+CD62LhiCD25- T cells were sorted from the spleens and lymph nodes of C57BL6/J mice. They were stimulated with plate-bound anti-CD3+anti-CD28 under Th1 or Th17 conditions, with the indicated concentrations of IFN-β, for 48 hours, and cell lysates were generated. A. Expression of Stat1 and pStat1(Y701) were assessed by Western blot. Representative of two experiments. B. Expression of Stat4 and pStat4(Y693) were assessed by Western blot. Representative of three experiments. GAPDH, loading control.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4401451&req=5

pone.0124802.g005: IFN-β regulates Stat1 and Stat4 expression on Th cells in the absence of APCs.CD4+CD62LhiCD25- T cells were sorted from the spleens and lymph nodes of C57BL6/J mice. They were stimulated with plate-bound anti-CD3+anti-CD28 under Th1 or Th17 conditions, with the indicated concentrations of IFN-β, for 48 hours, and cell lysates were generated. A. Expression of Stat1 and pStat1(Y701) were assessed by Western blot. Representative of two experiments. B. Expression of Stat4 and pStat4(Y693) were assessed by Western blot. Representative of three experiments. GAPDH, loading control.
Mentions: Stat1 and Stat4 are transcription factors that are crucial to initial steps in Th1 cell differentiation. Stat1 is phosphorylated upon T cell exposure to IFN-γ, while Stat4 activity is induced by IL-12 [42]. As our data indicate that IFN-β can modulate Th1 cell function in vitro and in vivo, we wanted to examine its effects on Stat1 and Stat4 activity in Th1 cells. To our surprise, we found that IFN-β strongly induced Stat1 phosphorylation at tyrosine residue 701 (Y701) in Th1 and Th17 cells. (Fig 5A). It was previously demonstrated that Th17 differentiation conditions can induce Stat1 [43]. By contrast, phosphorylation of Stat4 at Y693 in Th1 cells was markedly reduced by IFN-β (Fig 5B). These data suggest that while IFN-β can enhance sensitivity of Th1 cells to IFN-γ, it downmodulates their response to the key Th1 differentiation cytokine IL-12.

Bottom Line: CD4+ T cells express the type I interferon receptor, and IFN-β can suppress Th1 cell proliferation under APC-free stimulation conditions.Further, IFN-β treatment of Th1 cells upregulates phosphorylation of Stat1, and downregulates phosphorylation of Stat4.Our data indicate that IFN-γ-producing Th1 cells are directly responsive to IFN-β and point to a novel mechanism of IFN-β-mediated T cell suppression that is independent of APC-derived signals.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, Centre de recherche du CHU de Québec-Université Laval, Québec QC, Canada G1V 4G2.

ABSTRACT
Interferon (IFN)-β is a front-line therapy for the treatment of the relapsing-remitting form of multiple sclerosis. However, its immunosuppressive mechanism of function remains incompletely understood. While it has been proposed that IFN-β suppresses the function of inflammatory myelin antigen-reactive T cells by promoting the release of immunomodulatory cytokines such as IL-27 from antigen-presenting cells (APCs), its direct effects on inflammatory CD4+ Th1 cells are less clear. Here, we establish that IFN-β inhibits mouse IFN-γ+ Th1 cell function in the absence of APCs. CD4+ T cells express the type I interferon receptor, and IFN-β can suppress Th1 cell proliferation under APC-free stimulation conditions. IFN-β-treated myelin antigen-specific Th1 cells are impaired in their ability to induce severe experimental autoimmune encephalomyelitis (EAE) upon transfer to lymphocyte-deficient Rag1-/- mice. Polarized Th1 cells downregulate IFN-γ and IL-2, and upregulate the negative regulatory receptor Tim-3, when treated with IFN-β in the absence of APCs. Further, IFN-β treatment of Th1 cells upregulates phosphorylation of Stat1, and downregulates phosphorylation of Stat4. Our data indicate that IFN-γ-producing Th1 cells are directly responsive to IFN-β and point to a novel mechanism of IFN-β-mediated T cell suppression that is independent of APC-derived signals.

No MeSH data available.


Related in: MedlinePlus