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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 the encephalitogenic potential of Th1 cells.CD4+CD62Lhi T cells were isolated from female 2D2 mouse spleens and lymph nodes, and were stimulated with plate-bound anti-CD3+anti-CD28 under Th1 conditions, in the presence or absence of 100 U mL-1 of IFN-β, for 5 days. They were then transferred to female, 6-week old, Rag1-/- mice (5x106 cells/mouse). Recipient mice were monitored for clinical signs of EAE. n = 5 Th1, n = 4 Th1+IFN-β. Right graph, linear regression curves of the disease courses. The slopes are significantly different between the disease courses (p<0.0006). B. Brains and spinal cords were isolated from mice in (A) at d32 and single mononuclear cell suspensions were obtained. The frequency of CNS-infiltrating CD4+ cells was assessed by flow cytometry. * p<0.05, two-tailed Student’s t test.
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pone.0124802.g003: IFN-β suppresses the encephalitogenic potential of Th1 cells.CD4+CD62Lhi T cells were isolated from female 2D2 mouse spleens and lymph nodes, and were stimulated with plate-bound anti-CD3+anti-CD28 under Th1 conditions, in the presence or absence of 100 U mL-1 of IFN-β, for 5 days. They were then transferred to female, 6-week old, Rag1-/- mice (5x106 cells/mouse). Recipient mice were monitored for clinical signs of EAE. n = 5 Th1, n = 4 Th1+IFN-β. Right graph, linear regression curves of the disease courses. The slopes are significantly different between the disease courses (p<0.0006). B. Brains and spinal cords were isolated from mice in (A) at d32 and single mononuclear cell suspensions were obtained. The frequency of CNS-infiltrating CD4+ cells was assessed by flow cytometry. * p<0.05, two-tailed Student’s t test.

Mentions: It was recently suggested that IFN-β selectively inhibits Th1-mediated CNS autoimmunity and antigen-specific Th1 responses in mice [18]. In this study, mice that had received myelin antigen-specific effector Th1 cells were subsequently injected with recombinant IFN-β over the course of the disease. Thus, it remains unclear whether IFN-β can directly inhibit myelin-specific Th1 cell responses, or whether the effects of IFN-β on Th1 cells in EAE are the indirect result of IFN-β acting on bystander APCs. To isolate the direct effects of IFN-β on the encephalitogenic potential of myelin-reactive T cells, we exploited a recently described model of myelin antigen-specific T cell transfer in which myelin oligodendrocyte glycoprotein (MOG)[35–55]-specific transgenic CD4+ T cells (2D2 cells) are stimulated in vitro under defined differentiation conditions and are then transferred to non-immunized recipients to induce EAE [35]. We sorted CD4+CD62Lhi T cells from 2D2 mice [25] and stimulated them with anti-CD3+anti-CD28 under Th1 differentiation conditions, in the presence or absence of IFN-β. After 5 days of culture under Th1 conditions, cells were transferred to lymphocyte-deficient Rag1-/- recipients. These mice were then monitored for the development of EAE. We found that recipients of IFN-β-treated 2D2 Th1 cells developed EAE of lessened severity when compared to mice that received 2D2 Th1 cells that had not been cultured with IFN-β (Fig 3A). Further, the percentage of CNS-infiltrating CD4+ T cells was lower in IFN-β-treated 2D2 recipients than in control 2D2 recipients (Fig 3B). Taken together, these data indicate that exposure to IFN-β during the priming phase of T cell stimulation can diminish the capacity of Th1 cells to infiltrate the CNS and induce EAE.


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 the encephalitogenic potential of Th1 cells.CD4+CD62Lhi T cells were isolated from female 2D2 mouse spleens and lymph nodes, and were stimulated with plate-bound anti-CD3+anti-CD28 under Th1 conditions, in the presence or absence of 100 U mL-1 of IFN-β, for 5 days. They were then transferred to female, 6-week old, Rag1-/- mice (5x106 cells/mouse). Recipient mice were monitored for clinical signs of EAE. n = 5 Th1, n = 4 Th1+IFN-β. Right graph, linear regression curves of the disease courses. The slopes are significantly different between the disease courses (p<0.0006). B. Brains and spinal cords were isolated from mice in (A) at d32 and single mononuclear cell suspensions were obtained. The frequency of CNS-infiltrating CD4+ cells was assessed by flow cytometry. * p<0.05, two-tailed Student’s t test.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0124802.g003: IFN-β suppresses the encephalitogenic potential of Th1 cells.CD4+CD62Lhi T cells were isolated from female 2D2 mouse spleens and lymph nodes, and were stimulated with plate-bound anti-CD3+anti-CD28 under Th1 conditions, in the presence or absence of 100 U mL-1 of IFN-β, for 5 days. They were then transferred to female, 6-week old, Rag1-/- mice (5x106 cells/mouse). Recipient mice were monitored for clinical signs of EAE. n = 5 Th1, n = 4 Th1+IFN-β. Right graph, linear regression curves of the disease courses. The slopes are significantly different between the disease courses (p<0.0006). B. Brains and spinal cords were isolated from mice in (A) at d32 and single mononuclear cell suspensions were obtained. The frequency of CNS-infiltrating CD4+ cells was assessed by flow cytometry. * p<0.05, two-tailed Student’s t test.
Mentions: It was recently suggested that IFN-β selectively inhibits Th1-mediated CNS autoimmunity and antigen-specific Th1 responses in mice [18]. In this study, mice that had received myelin antigen-specific effector Th1 cells were subsequently injected with recombinant IFN-β over the course of the disease. Thus, it remains unclear whether IFN-β can directly inhibit myelin-specific Th1 cell responses, or whether the effects of IFN-β on Th1 cells in EAE are the indirect result of IFN-β acting on bystander APCs. To isolate the direct effects of IFN-β on the encephalitogenic potential of myelin-reactive T cells, we exploited a recently described model of myelin antigen-specific T cell transfer in which myelin oligodendrocyte glycoprotein (MOG)[35–55]-specific transgenic CD4+ T cells (2D2 cells) are stimulated in vitro under defined differentiation conditions and are then transferred to non-immunized recipients to induce EAE [35]. We sorted CD4+CD62Lhi T cells from 2D2 mice [25] and stimulated them with anti-CD3+anti-CD28 under Th1 differentiation conditions, in the presence or absence of IFN-β. After 5 days of culture under Th1 conditions, cells were transferred to lymphocyte-deficient Rag1-/- recipients. These mice were then monitored for the development of EAE. We found that recipients of IFN-β-treated 2D2 Th1 cells developed EAE of lessened severity when compared to mice that received 2D2 Th1 cells that had not been cultured with IFN-β (Fig 3A). Further, the percentage of CNS-infiltrating CD4+ T cells was lower in IFN-β-treated 2D2 recipients than in control 2D2 recipients (Fig 3B). Taken together, these data indicate that exposure to IFN-β during the priming phase of T cell stimulation can diminish the capacity of Th1 cells to infiltrate the CNS and induce EAE.

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