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GM-CSF mediates autoimmunity by enhancing IL-6-dependent Th17 cell development and survival.

Sonderegger I, Iezzi G, Maier R, Schmitz N, Kurrer M, Kopf M - J. Exp. Med. (2008)

Bottom Line: Roles of GM-CSF in the initiation and in the effector phase of the autoimmune response have been proposed.We found that innate GM-CSF was critical for IL-6 and IL-23 responses by dendritic cells and generation of pathological Th17 cells in vivo.These results suggest a novel role for GM-CSF in promoting generation and maintenance of Th17 cells by regulation of IL-6 and IL-23 in vivo.

View Article: PubMed Central - PubMed

Affiliation: Institute of Integrative Biology, Molecular Biomedicine, ETH Zürich, 8952 Zürich, Switzerland.

ABSTRACT
Granulocyte macrophage-colony stimulating factor (GM-CSF) is critically involved in development of organ-related autoimmune inflammatory diseases including experimental allergic encephalitis and collagen-induced arthritis. Roles of GM-CSF in the initiation and in the effector phase of the autoimmune response have been proposed. Our study was designed to investigate the mechanisms of GM-CSF in autoimmunity using a model of autoimmune heart inflammatory disease (myocarditis). The pathological sequel after immunization with heart myosin has been shown previously to depend on IL-1, IL-6, IL-23, and IL-17. We found that innate GM-CSF was critical for IL-6 and IL-23 responses by dendritic cells and generation of pathological Th17 cells in vivo. Moreover, GM-CSF promoted autoimmunity by enhancing IL-6-dependent survival of antigen specific CD4(+) T cells. These results suggest a novel role for GM-CSF in promoting generation and maintenance of Th17 cells by regulation of IL-6 and IL-23 in vivo.

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GM-CSF−/− mice show reduced frequencies of IL-17+IFN-γ− and IL-17+IFN-γ+ CD4+ T cell populations. (A) CD4+ T cells purified from DO11.10/GM-CSF+/+ or DO11.10/GM-CSF−/− mice were adoptively transferred to GM-CSF+/+ or GM-CSF−/− mice, respectively, 2 d prior to immunization with 200 μg OVA323-339 peptide emulsified in CFA. Mice were boosted at day 7 and draining LN were removed at day 14 to determine KJ1-26+ CD4+ T cells producing IL-17 or IFN-γ by flow cytometry. Top shows dot plots of a representative mouse per group. Bottom shows the frequency of cytokine-producing cells in individual mice. (B and C) GM-CSF−/− and GM-CSF+/+ mice were immunized with myhcα614-629/CFA at days 0 and 7. (B) IL-17 and IFN-γ expression was determined by real-time PCR using cDNA from CD4+ T cells purified from draining LN at day 8. Values show means of groups (n = 3) of mice ±SD. (C) At day 14, CD4+ T cells were isolated from LN and restimulated with myhcα614-629 as described in Materials and methods. IFN-γ– and IL-17–producing cells were determined by ELISPOT analysis. Values indicate individual mice and means of groups.
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fig7: GM-CSF−/− mice show reduced frequencies of IL-17+IFN-γ− and IL-17+IFN-γ+ CD4+ T cell populations. (A) CD4+ T cells purified from DO11.10/GM-CSF+/+ or DO11.10/GM-CSF−/− mice were adoptively transferred to GM-CSF+/+ or GM-CSF−/− mice, respectively, 2 d prior to immunization with 200 μg OVA323-339 peptide emulsified in CFA. Mice were boosted at day 7 and draining LN were removed at day 14 to determine KJ1-26+ CD4+ T cells producing IL-17 or IFN-γ by flow cytometry. Top shows dot plots of a representative mouse per group. Bottom shows the frequency of cytokine-producing cells in individual mice. (B and C) GM-CSF−/− and GM-CSF+/+ mice were immunized with myhcα614-629/CFA at days 0 and 7. (B) IL-17 and IFN-γ expression was determined by real-time PCR using cDNA from CD4+ T cells purified from draining LN at day 8. Values show means of groups (n = 3) of mice ±SD. (C) At day 14, CD4+ T cells were isolated from LN and restimulated with myhcα614-629 as described in Materials and methods. IFN-γ– and IL-17–producing cells were determined by ELISPOT analysis. Values indicate individual mice and means of groups.

Mentions: IL-6 and IL-23 are key factors for development, maintenance, and pathogenicity of IL-17–producing CD4+ T (Th17) cells. Considering the defect of GM-CSF−/− CD4+ T cells in producing IL-17 in vitro, we studied Th17 development in GM-CSF−/− mice in vivo. To this end, we transferred DO11.10/GM-CSF−/− and DO11.10/GM-CSF+/+ CD4+ T cells to KO and WT mice, respectively. Immunization with OVA323-339/CFA resulted in a high frequency of IL-17+IFN-γ− (Th17) cells and lower frequencies of IFN-γ+IL-17− (Th1) and IL-17+IFN-γ+ coproducers among OVA-specific CD4+ T cells in GM-CSF–competent mice. Th17 and IL-17+IFN-γ+ CD4 populations were strikingly reduced, whereas frequencies of Th1 cells were unaffected in GM-CSF−/− mice (Fig. 7 B). Thus, GM-CSF was critical for development and survival of IL-17–producing cells upon immunization with antigen in CFA in vivo.


GM-CSF mediates autoimmunity by enhancing IL-6-dependent Th17 cell development and survival.

Sonderegger I, Iezzi G, Maier R, Schmitz N, Kurrer M, Kopf M - J. Exp. Med. (2008)

GM-CSF−/− mice show reduced frequencies of IL-17+IFN-γ− and IL-17+IFN-γ+ CD4+ T cell populations. (A) CD4+ T cells purified from DO11.10/GM-CSF+/+ or DO11.10/GM-CSF−/− mice were adoptively transferred to GM-CSF+/+ or GM-CSF−/− mice, respectively, 2 d prior to immunization with 200 μg OVA323-339 peptide emulsified in CFA. Mice were boosted at day 7 and draining LN were removed at day 14 to determine KJ1-26+ CD4+ T cells producing IL-17 or IFN-γ by flow cytometry. Top shows dot plots of a representative mouse per group. Bottom shows the frequency of cytokine-producing cells in individual mice. (B and C) GM-CSF−/− and GM-CSF+/+ mice were immunized with myhcα614-629/CFA at days 0 and 7. (B) IL-17 and IFN-γ expression was determined by real-time PCR using cDNA from CD4+ T cells purified from draining LN at day 8. Values show means of groups (n = 3) of mice ±SD. (C) At day 14, CD4+ T cells were isolated from LN and restimulated with myhcα614-629 as described in Materials and methods. IFN-γ– and IL-17–producing cells were determined by ELISPOT analysis. Values indicate individual mice and means of groups.
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fig7: GM-CSF−/− mice show reduced frequencies of IL-17+IFN-γ− and IL-17+IFN-γ+ CD4+ T cell populations. (A) CD4+ T cells purified from DO11.10/GM-CSF+/+ or DO11.10/GM-CSF−/− mice were adoptively transferred to GM-CSF+/+ or GM-CSF−/− mice, respectively, 2 d prior to immunization with 200 μg OVA323-339 peptide emulsified in CFA. Mice were boosted at day 7 and draining LN were removed at day 14 to determine KJ1-26+ CD4+ T cells producing IL-17 or IFN-γ by flow cytometry. Top shows dot plots of a representative mouse per group. Bottom shows the frequency of cytokine-producing cells in individual mice. (B and C) GM-CSF−/− and GM-CSF+/+ mice were immunized with myhcα614-629/CFA at days 0 and 7. (B) IL-17 and IFN-γ expression was determined by real-time PCR using cDNA from CD4+ T cells purified from draining LN at day 8. Values show means of groups (n = 3) of mice ±SD. (C) At day 14, CD4+ T cells were isolated from LN and restimulated with myhcα614-629 as described in Materials and methods. IFN-γ– and IL-17–producing cells were determined by ELISPOT analysis. Values indicate individual mice and means of groups.
Mentions: IL-6 and IL-23 are key factors for development, maintenance, and pathogenicity of IL-17–producing CD4+ T (Th17) cells. Considering the defect of GM-CSF−/− CD4+ T cells in producing IL-17 in vitro, we studied Th17 development in GM-CSF−/− mice in vivo. To this end, we transferred DO11.10/GM-CSF−/− and DO11.10/GM-CSF+/+ CD4+ T cells to KO and WT mice, respectively. Immunization with OVA323-339/CFA resulted in a high frequency of IL-17+IFN-γ− (Th17) cells and lower frequencies of IFN-γ+IL-17− (Th1) and IL-17+IFN-γ+ coproducers among OVA-specific CD4+ T cells in GM-CSF–competent mice. Th17 and IL-17+IFN-γ+ CD4 populations were strikingly reduced, whereas frequencies of Th1 cells were unaffected in GM-CSF−/− mice (Fig. 7 B). Thus, GM-CSF was critical for development and survival of IL-17–producing cells upon immunization with antigen in CFA in vivo.

Bottom Line: Roles of GM-CSF in the initiation and in the effector phase of the autoimmune response have been proposed.We found that innate GM-CSF was critical for IL-6 and IL-23 responses by dendritic cells and generation of pathological Th17 cells in vivo.These results suggest a novel role for GM-CSF in promoting generation and maintenance of Th17 cells by regulation of IL-6 and IL-23 in vivo.

View Article: PubMed Central - PubMed

Affiliation: Institute of Integrative Biology, Molecular Biomedicine, ETH Zürich, 8952 Zürich, Switzerland.

ABSTRACT
Granulocyte macrophage-colony stimulating factor (GM-CSF) is critically involved in development of organ-related autoimmune inflammatory diseases including experimental allergic encephalitis and collagen-induced arthritis. Roles of GM-CSF in the initiation and in the effector phase of the autoimmune response have been proposed. Our study was designed to investigate the mechanisms of GM-CSF in autoimmunity using a model of autoimmune heart inflammatory disease (myocarditis). The pathological sequel after immunization with heart myosin has been shown previously to depend on IL-1, IL-6, IL-23, and IL-17. We found that innate GM-CSF was critical for IL-6 and IL-23 responses by dendritic cells and generation of pathological Th17 cells in vivo. Moreover, GM-CSF promoted autoimmunity by enhancing IL-6-dependent survival of antigen specific CD4(+) T cells. These results suggest a novel role for GM-CSF in promoting generation and maintenance of Th17 cells by regulation of IL-6 and IL-23 in vivo.

Show MeSH
Related in: MedlinePlus