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Interferon-╬▓ 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 Qu├ębec-Universit├ę Laval, Qu├ębec QC, Canada G1V 4G2.

ABSTRACT
Interferon (IFN)-╬▓ 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-╬▓ 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-╬▓ inhibits mouse IFN-╬│+ Th1 cell function in the absence of APCs. CD4+ T cells express the type I interferon receptor, and IFN-╬▓ can suppress Th1 cell proliferation under APC-free stimulation conditions. IFN-╬▓-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-╬│ and IL-2, and upregulate the negative regulatory receptor Tim-3, when treated with IFN-╬▓ in the absence of APCs. Further, IFN-╬▓ treatment of Th1 cells upregulates phosphorylation of Stat1, and downregulates phosphorylation of Stat4. Our data indicate that IFN-╬│-producing Th1 cells are directly responsive to IFN-╬▓ and point to a novel mechanism of IFN-╬▓-mediated T cell suppression that is independent of APC-derived signals.

No MeSH data available.


Related in: MedlinePlus

Th1 cells express the type I interferon receptor.A. Naïve (CD62Lhi) and effector (CD62Llo) CD4+ and CD8+ C57BL/6J T cells were assessed for surface expression of Ifnar1 by flow cytometry. Open histogram, Ifnar1; shaded histogram, fluorescence minus one (FMO) control. B. Th1 and Th17 cells were cultured and assessed for surface expression of Ifnar1 after 5 days. Solid line with open histogram, Th1; Dotted line with open histogram, Th17; shaded histogram, FMO control. Data representative of one of three experiments.
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pone.0124802.g001: Th1 cells express the type I interferon receptor.A. Naïve (CD62Lhi) and effector (CD62Llo) CD4+ and CD8+ C57BL/6J T cells were assessed for surface expression of Ifnar1 by flow cytometry. Open histogram, Ifnar1; shaded histogram, fluorescence minus one (FMO) control. B. Th1 and Th17 cells were cultured and assessed for surface expression of Ifnar1 after 5 days. Solid line with open histogram, Th1; Dotted line with open histogram, Th17; shaded histogram, FMO control. Data representative of one of three experiments.

Mentions: IFN-β signals through the IFN-α/β receptor (IFN-α/β-R), which consists of receptor chains 1 and 2. We first sought to confirm that CD4+ T cells express the IFN-αR complex. As expression of IFN-α/β-R on CD8+ T cells is critical for the ability of mice to clear vaccinia virus and lymphocytic choriomeningitis virus infection [30], we also assessed CD8+ T cell expression of IFN-α/β-R in parallel. We found that CD4+ T cells from unmanipulated mice express Ifnar1 on their surface at levels comparable to those seen in CD8+ T cells. Both naïve (CD62Lhi) and effector (CD62Llo) T cells express IFN-α/β-R, suggesting that T cells are potentially responsive to IFN-β at multiple stages of differentiation (Fig 1A). As both Th1 and Th17 responses are implicated in the pathogenesis of MS and EAE [8,9], we wanted to assess the expression of Ifnar1 on Th1 and Th17 cells. We found that in vitro differentiated Th1 cells expressed higher levels of Ifnar1 than their Th17 counterparts (Fig 1B).


Interferon-╬▓ 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)

Th1 cells express the type I interferon receptor.A. Naïve (CD62Lhi) and effector (CD62Llo) CD4+ and CD8+ C57BL/6J T cells were assessed for surface expression of Ifnar1 by flow cytometry. Open histogram, Ifnar1; shaded histogram, fluorescence minus one (FMO) control. B. Th1 and Th17 cells were cultured and assessed for surface expression of Ifnar1 after 5 days. Solid line with open histogram, Th1; Dotted line with open histogram, Th17; shaded histogram, FMO control. Data representative of one of three experiments.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0124802.g001: Th1 cells express the type I interferon receptor.A. Naïve (CD62Lhi) and effector (CD62Llo) CD4+ and CD8+ C57BL/6J T cells were assessed for surface expression of Ifnar1 by flow cytometry. Open histogram, Ifnar1; shaded histogram, fluorescence minus one (FMO) control. B. Th1 and Th17 cells were cultured and assessed for surface expression of Ifnar1 after 5 days. Solid line with open histogram, Th1; Dotted line with open histogram, Th17; shaded histogram, FMO control. Data representative of one of three experiments.
Mentions: IFN-β signals through the IFN-α/β receptor (IFN-α/β-R), which consists of receptor chains 1 and 2. We first sought to confirm that CD4+ T cells express the IFN-αR complex. As expression of IFN-α/β-R on CD8+ T cells is critical for the ability of mice to clear vaccinia virus and lymphocytic choriomeningitis virus infection [30], we also assessed CD8+ T cell expression of IFN-α/β-R in parallel. We found that CD4+ T cells from unmanipulated mice express Ifnar1 on their surface at levels comparable to those seen in CD8+ T cells. Both naïve (CD62Lhi) and effector (CD62Llo) T cells express IFN-α/β-R, suggesting that T cells are potentially responsive to IFN-β at multiple stages of differentiation (Fig 1A). As both Th1 and Th17 responses are implicated in the pathogenesis of MS and EAE [8,9], we wanted to assess the expression of Ifnar1 on Th1 and Th17 cells. We found that in vitro differentiated Th1 cells expressed higher levels of Ifnar1 than their Th17 counterparts (Fig 1B).

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 Qu├ębec-Universit├ę Laval, Qu├ębec QC, Canada G1V 4G2.

ABSTRACT
Interferon (IFN)-╬▓ 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-╬▓ 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-╬▓ inhibits mouse IFN-╬│+ Th1 cell function in the absence of APCs. CD4+ T cells express the type I interferon receptor, and IFN-╬▓ can suppress Th1 cell proliferation under APC-free stimulation conditions. IFN-╬▓-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-╬│ and IL-2, and upregulate the negative regulatory receptor Tim-3, when treated with IFN-╬▓ in the absence of APCs. Further, IFN-╬▓ treatment of Th1 cells upregulates phosphorylation of Stat1, and downregulates phosphorylation of Stat4. Our data indicate that IFN-╬│-producing Th1 cells are directly responsive to IFN-╬▓ and point to a novel mechanism of IFN-╬▓-mediated T cell suppression that is independent of APC-derived signals.

No MeSH data available.


Related in: MedlinePlus