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Role of Tyk-2 in Th9 and Th17 cells in allergic asthma.

Übel C, Graser A, Koch S, Rieker RJ, Lehr HA, Müller M, Finotto S - Sci Rep (2014)

Bottom Line: In a murine model of allergic asthma, we found that Tyk-2((-/-)) asthmatic mice have induced peribronchial collagen deposition, mucosal type mast cells in the lung, IRF4 and hyperproliferative lung Th2 CD4(+) effector T cells over-expressing IL-3, IL-4, IL-5, IL-10 and IL-13.We also observed increased Th9 cells expressing IL-9 and IL-10 as well as T helper cells expressing IL-6, IL-10 and IL-21 with a defect in IL-17A and IL-17F production.Finally, in vivo treatment with rIL-17A inhibited local CD4(+)CD25(+)Foxp3(+) T regulatory cells as well as Th2 cytokines without affecting IL-9 in the lung.

View Article: PubMed Central - PubMed

Affiliation: 1] Laboratory of Cellular and Molecular Immunology of the Lung, Institute of Molecular Pneumology, University of Erlangen-Nürnberg, 91054 Erlangen, Germany [2].

ABSTRACT
In a murine model of allergic asthma, we found that Tyk-2((-/-)) asthmatic mice have induced peribronchial collagen deposition, mucosal type mast cells in the lung, IRF4 and hyperproliferative lung Th2 CD4(+) effector T cells over-expressing IL-3, IL-4, IL-5, IL-10 and IL-13. We also observed increased Th9 cells expressing IL-9 and IL-10 as well as T helper cells expressing IL-6, IL-10 and IL-21 with a defect in IL-17A and IL-17F production. This T helper phenotype was accompanied by increased SOCS3 in the lung of Tyk-2 deficient asthmatic mice. Finally, in vivo treatment with rIL-17A inhibited local CD4(+)CD25(+)Foxp3(+) T regulatory cells as well as Th2 cytokines without affecting IL-9 in the lung. These results suggest a role of Tyk-2 in different subsets of T helper cells mediated by SOCS3 regulation that is relevant for the treatment of asthma, cancer and autoimmune diseases.

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Tyk-2(−/−) naïve CD4+ T cells showed a defective Th17 cytokine production ex vivo.Spleen CD4+CD62L+ T cells were isolated from naïve Tyk-2(−/−) and wild-type mice and treated with antibodies against CD3 (2 μg/ml), CD28 (2 μg/ml), IL-4 (10 μg/ml) and IFNγ (10 μg/ml) while recombinant cytokines TGF-β (3 ng/ml), IL-6 (20 ng/ml), IL-23 (50 ng/ml) and IL-21 (80 ng/ml) were added as indicated. After five days the supernatant was collected and analyzed by ELISA for IL-17A ((a): n = 2, p = 0,004, p = 0,009, p = 0,0008, p = 0,0003, p = 0,006) IL-10 ((b): n = 2, p = 0,003) and IL-17F ((c): n = 2, p = 0,001, p = 0,004, p = 0,0003).
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f4: Tyk-2(−/−) naïve CD4+ T cells showed a defective Th17 cytokine production ex vivo.Spleen CD4+CD62L+ T cells were isolated from naïve Tyk-2(−/−) and wild-type mice and treated with antibodies against CD3 (2 μg/ml), CD28 (2 μg/ml), IL-4 (10 μg/ml) and IFNγ (10 μg/ml) while recombinant cytokines TGF-β (3 ng/ml), IL-6 (20 ng/ml), IL-23 (50 ng/ml) and IL-21 (80 ng/ml) were added as indicated. After five days the supernatant was collected and analyzed by ELISA for IL-17A ((a): n = 2, p = 0,004, p = 0,009, p = 0,0008, p = 0,0003, p = 0,006) IL-10 ((b): n = 2, p = 0,003) and IL-17F ((c): n = 2, p = 0,001, p = 0,004, p = 0,0003).

Mentions: Tyk-2 is located downstream of IL-6 and IL-23 signaling that are crucially involved in the generation and proliferation of Th17 cells43031. We thus wanted to determine whether alternative pathways were involved in the development of Th17 cells in the absence of Tyk-2. To this aim we isolated splenic CD4+CD62L+ T cells and exposed them to Th17 skewing cell culture conditions (α-CD3, α-CD28, α-IL-4, α-IFNγ antibodies) in the presence of either IL-6 or either IL-21 or IL-23 and TGF-β (Fig. 4a). Under all these experimental conditions IL-17A production was found significantly reduced in naïve CD4+ T cells isolated from Tyk-2(−/−) mice as compared to cells isolated from the wild type littermates regardless of the cytokine milieu.


Role of Tyk-2 in Th9 and Th17 cells in allergic asthma.

Übel C, Graser A, Koch S, Rieker RJ, Lehr HA, Müller M, Finotto S - Sci Rep (2014)

Tyk-2(−/−) naïve CD4+ T cells showed a defective Th17 cytokine production ex vivo.Spleen CD4+CD62L+ T cells were isolated from naïve Tyk-2(−/−) and wild-type mice and treated with antibodies against CD3 (2 μg/ml), CD28 (2 μg/ml), IL-4 (10 μg/ml) and IFNγ (10 μg/ml) while recombinant cytokines TGF-β (3 ng/ml), IL-6 (20 ng/ml), IL-23 (50 ng/ml) and IL-21 (80 ng/ml) were added as indicated. After five days the supernatant was collected and analyzed by ELISA for IL-17A ((a): n = 2, p = 0,004, p = 0,009, p = 0,0008, p = 0,0003, p = 0,006) IL-10 ((b): n = 2, p = 0,003) and IL-17F ((c): n = 2, p = 0,001, p = 0,004, p = 0,0003).
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4127519&req=5

f4: Tyk-2(−/−) naïve CD4+ T cells showed a defective Th17 cytokine production ex vivo.Spleen CD4+CD62L+ T cells were isolated from naïve Tyk-2(−/−) and wild-type mice and treated with antibodies against CD3 (2 μg/ml), CD28 (2 μg/ml), IL-4 (10 μg/ml) and IFNγ (10 μg/ml) while recombinant cytokines TGF-β (3 ng/ml), IL-6 (20 ng/ml), IL-23 (50 ng/ml) and IL-21 (80 ng/ml) were added as indicated. After five days the supernatant was collected and analyzed by ELISA for IL-17A ((a): n = 2, p = 0,004, p = 0,009, p = 0,0008, p = 0,0003, p = 0,006) IL-10 ((b): n = 2, p = 0,003) and IL-17F ((c): n = 2, p = 0,001, p = 0,004, p = 0,0003).
Mentions: Tyk-2 is located downstream of IL-6 and IL-23 signaling that are crucially involved in the generation and proliferation of Th17 cells43031. We thus wanted to determine whether alternative pathways were involved in the development of Th17 cells in the absence of Tyk-2. To this aim we isolated splenic CD4+CD62L+ T cells and exposed them to Th17 skewing cell culture conditions (α-CD3, α-CD28, α-IL-4, α-IFNγ antibodies) in the presence of either IL-6 or either IL-21 or IL-23 and TGF-β (Fig. 4a). Under all these experimental conditions IL-17A production was found significantly reduced in naïve CD4+ T cells isolated from Tyk-2(−/−) mice as compared to cells isolated from the wild type littermates regardless of the cytokine milieu.

Bottom Line: In a murine model of allergic asthma, we found that Tyk-2((-/-)) asthmatic mice have induced peribronchial collagen deposition, mucosal type mast cells in the lung, IRF4 and hyperproliferative lung Th2 CD4(+) effector T cells over-expressing IL-3, IL-4, IL-5, IL-10 and IL-13.We also observed increased Th9 cells expressing IL-9 and IL-10 as well as T helper cells expressing IL-6, IL-10 and IL-21 with a defect in IL-17A and IL-17F production.Finally, in vivo treatment with rIL-17A inhibited local CD4(+)CD25(+)Foxp3(+) T regulatory cells as well as Th2 cytokines without affecting IL-9 in the lung.

View Article: PubMed Central - PubMed

Affiliation: 1] Laboratory of Cellular and Molecular Immunology of the Lung, Institute of Molecular Pneumology, University of Erlangen-Nürnberg, 91054 Erlangen, Germany [2].

ABSTRACT
In a murine model of allergic asthma, we found that Tyk-2((-/-)) asthmatic mice have induced peribronchial collagen deposition, mucosal type mast cells in the lung, IRF4 and hyperproliferative lung Th2 CD4(+) effector T cells over-expressing IL-3, IL-4, IL-5, IL-10 and IL-13. We also observed increased Th9 cells expressing IL-9 and IL-10 as well as T helper cells expressing IL-6, IL-10 and IL-21 with a defect in IL-17A and IL-17F production. This T helper phenotype was accompanied by increased SOCS3 in the lung of Tyk-2 deficient asthmatic mice. Finally, in vivo treatment with rIL-17A inhibited local CD4(+)CD25(+)Foxp3(+) T regulatory cells as well as Th2 cytokines without affecting IL-9 in the lung. These results suggest a role of Tyk-2 in different subsets of T helper cells mediated by SOCS3 regulation that is relevant for the treatment of asthma, cancer and autoimmune diseases.

Show MeSH
Related in: MedlinePlus