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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 suppresses cytokine secretion from Th1 cells.A. CD4+CD62Lhi T cells were sorted from the spleens and lymph nodes of C57BL6/J mice and were stimulated with plate-bound anti-CD3+anti-CD28 under Th1 conditions, with the indicated concentrations of IFN-β, for 5 days. Cells were restimulated for 48 hours under Th1 conditions with the same concentration of IFN-β as at the initial stimulation. A. Generation of IFN-γ and IL-2 was assessed by intracellular cytokine staining and flow cytometry. Representative of three experiments. B. Expression of Tim-3 and PD-1 were assessed by flow cytometry. Representative of three experiments. C. Expression of T-bet was assessed by flow cytometry. Representative data from one of three mice assessed individually. Solid line with open histogram, Th1; dashed line with open histogram, Th1 + 10 U mL-1 IFN-β; dotted line with open histogram, Th1 + 100 U mL-1 IFN-β; shaded histogram, FMO control. Data in all panels gated on CD4+ cells.
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pone.0124802.g004: IFN-β suppresses cytokine secretion from Th1 cells.A. CD4+CD62Lhi T cells were sorted from the spleens and lymph nodes of C57BL6/J mice and were stimulated with plate-bound anti-CD3+anti-CD28 under Th1 conditions, with the indicated concentrations of IFN-β, for 5 days. Cells were restimulated for 48 hours under Th1 conditions with the same concentration of IFN-β as at the initial stimulation. A. Generation of IFN-γ and IL-2 was assessed by intracellular cytokine staining and flow cytometry. Representative of three experiments. B. Expression of Tim-3 and PD-1 were assessed by flow cytometry. Representative of three experiments. C. Expression of T-bet was assessed by flow cytometry. Representative data from one of three mice assessed individually. Solid line with open histogram, Th1; dashed line with open histogram, Th1 + 10 U mL-1 IFN-β; dotted line with open histogram, Th1 + 100 U mL-1 IFN-β; shaded histogram, FMO control. Data in all panels gated on CD4+ cells.

Mentions: Given our finding that IFN-β could suppress Th1 cell-mediated EAE through an APC-independent mechanism, we wished to more closely examine the effects of IFN-β on effector Th1 cell function. We generated Th1 cells from CD4+CD62Lhi naïve progenitors by plate-bound stimulation in the presence or absence of IFN-β. After 5 days, we restimulated the cells with plate-bound antibodies for an additional 48 hours in the continued presence or absence of IFN-β. We found that IFN-β reduced the percentage of polarized effector Th1 cells that generated IFN-γ and IL-2 as measured by flow cytometry (Fig 4A), demonstrating that IFN-β can downregulate an effector Th1 cell phenotype.


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 suppresses cytokine secretion from Th1 cells.A. CD4+CD62Lhi T cells were sorted from the spleens and lymph nodes of C57BL6/J mice and were stimulated with plate-bound anti-CD3+anti-CD28 under Th1 conditions, with the indicated concentrations of IFN-β, for 5 days. Cells were restimulated for 48 hours under Th1 conditions with the same concentration of IFN-β as at the initial stimulation. A. Generation of IFN-γ and IL-2 was assessed by intracellular cytokine staining and flow cytometry. Representative of three experiments. B. Expression of Tim-3 and PD-1 were assessed by flow cytometry. Representative of three experiments. C. Expression of T-bet was assessed by flow cytometry. Representative data from one of three mice assessed individually. Solid line with open histogram, Th1; dashed line with open histogram, Th1 + 10 U mL-1 IFN-β; dotted line with open histogram, Th1 + 100 U mL-1 IFN-β; shaded histogram, FMO control. Data in all panels gated on CD4+ cells.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0124802.g004: IFN-β suppresses cytokine secretion from Th1 cells.A. CD4+CD62Lhi T cells were sorted from the spleens and lymph nodes of C57BL6/J mice and were stimulated with plate-bound anti-CD3+anti-CD28 under Th1 conditions, with the indicated concentrations of IFN-β, for 5 days. Cells were restimulated for 48 hours under Th1 conditions with the same concentration of IFN-β as at the initial stimulation. A. Generation of IFN-γ and IL-2 was assessed by intracellular cytokine staining and flow cytometry. Representative of three experiments. B. Expression of Tim-3 and PD-1 were assessed by flow cytometry. Representative of three experiments. C. Expression of T-bet was assessed by flow cytometry. Representative data from one of three mice assessed individually. Solid line with open histogram, Th1; dashed line with open histogram, Th1 + 10 U mL-1 IFN-β; dotted line with open histogram, Th1 + 100 U mL-1 IFN-β; shaded histogram, FMO control. Data in all panels gated on CD4+ cells.
Mentions: Given our finding that IFN-β could suppress Th1 cell-mediated EAE through an APC-independent mechanism, we wished to more closely examine the effects of IFN-β on effector Th1 cell function. We generated Th1 cells from CD4+CD62Lhi naïve progenitors by plate-bound stimulation in the presence or absence of IFN-β. After 5 days, we restimulated the cells with plate-bound antibodies for an additional 48 hours in the continued presence or absence of IFN-β. We found that IFN-β reduced the percentage of polarized effector Th1 cells that generated IFN-γ and IL-2 as measured by flow cytometry (Fig 4A), demonstrating that IFN-β can downregulate an effector Th1 cell phenotype.

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