IL-17A and IL-17F do not contribute vitally to autoimmune neuro-inflammation in mice
Stefan Haak, Andrew L. Croxford, Katharina Kreymborg, Frank L. Heppner, Sandrine Pouly, Burkhard Becher, Ari Waisman
Stefan Haak, Andrew L. Croxford, Katharina Kreymborg, Frank L. Heppner, Sandrine Pouly, Burkhard Becher, Ari Waisman
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Research Article Autoimmunity

IL-17A and IL-17F do not contribute vitally to autoimmune neuro-inflammation in mice

Abstract

The clear association of Th17 cells with autoimmune pathogenicity implicates Th17 cytokines as critical mediators of chronic autoimmune diseases such as EAE. To study the impact of IL-17A on CNS inflammation, we generated transgenic mice in which high levels of expression of IL-17A could be initiated after Cre-mediated recombination. Although ubiquitous overexpression of IL-17A led to skin inflammation and granulocytosis, T cell–specific IL-17A overexpression did not have a perceptible impact on the development and health of the mice. In the context of EAE, neither the T cell–driven overexpression of IL-17A nor its complete loss had a major impact on the development of clinical disease. Since IL-17F may be able to compensate for the loss of IL-17A, we also generated IL-17F–deficient mice. This strain was fully susceptible to EAE and displayed unaltered emergence and expansion of autoreactive T cells during disease. To eliminate potential compensatory effects of either cytokine, we treated IL-17F–deficient mice with antagonistic monoclonal antibodies specific for IL-17A and found again only a minimal beneficial impact on disease development. We conclude therefore that both IL-17A and IL-17F, while prominently expressed by an encephalitogenic T cell population, may only marginally contribute to the development of autoimmune CNS disease.

Authors

Stefan Haak, Andrew L. Croxford, Katharina Kreymborg, Frank L. Heppner, Sandrine Pouly, Burkhard Becher, Ari Waisman

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Figure 5

Loss of IL-17F does not impact on T cell priming and does not lead to compensatory upregulation of IL-17A.

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Loss of IL-17F does not impact on T cell priming and does not lead to co...
(A–C) Mice were immunized with MOG35–55/CFA and lymphocytes were isolated from LNs prior to disease onset at 7 days after immunization. Cells were rechallenged with 50 μg/ml of MOG35–55, and IL-17A and IL-2 were measured by ELISA (A) and ELISPOT (B). (C) Proliferation of effector Th cells upon stimulation with MOG35–55 peptide or concanavalin A (ConA) was measured by thymidine incorporation. (A–C) A representative of 3 independent experiments is shown. Error bars indicate SEM of measured replicates. (D) Splenocytes from naive mice were polarized toward the Th17 effector type in vitro, and IL-17A, IL-17F, and IFN-γ were measured by intracellular cytokine staining. Dot plots are gated on Th cells (CD4+), and histograms are gated on Th17 cells (CD4+, IL-17A+). (E) Within the IL-17A–expressing Th17 compartment, IL-17F production is shown for each genotype. (F) CNS-infiltrating lymphocytes were isolated on day 24, after immunization from severely sick mice, restimulated with PMA/ionomycin and Brefeldin A for 5 hours, and analyzed for their IL-17A and IFN-γ expression by flow cytometry. (D–F) Percentages of gated cells are shown.