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Retinoic-acid-orphan-receptor-C inhibition suppresses Th17 cells and induces thymic aberrations
Christine Guntermann, … , Mark Deurinck, Jens Schümann
Christine Guntermann, … , Mark Deurinck, Jens Schümann
Published March 9, 2017
Citation Information: JCI Insight. 2017;2(5):e91127. https://doi.org/10.1172/jci.insight.91127.
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Research Article Immunology

Retinoic-acid-orphan-receptor-C inhibition suppresses Th17 cells and induces thymic aberrations

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Abstract

Retinoic-acid-orphan-receptor-C (RORC) is a master regulator of Th17 cells, which are pathogenic in several autoimmune diseases. Genetic Rorc deficiency in mice, while preventing autoimmunity, causes early lethality due to metastatic thymic T cell lymphomas. We sought to determine whether pharmacological RORC inhibition could be an effective and safe therapy for autoimmune diseases by evaluating its effects on Th17 cell functions and intrathymic T cell development. RORC inhibitors effectively inhibited Th17 differentiation and IL-17A production, and delayed-type hypersensitivity reactions. In vitro, RORC inhibitors induced apoptosis, as well as Bcl2l1 and BCL2L1 mRNA downregulation, in mouse and nonhuman primate thymocytes, respectively. Chronic, 13-week RORC inhibitor treatment in rats caused progressive thymic alterations in all analyzed rats similar to those in Rorc-deficient mice prior to T cell lymphoma development. One rat developed thymic cortical hyperplasia with preneoplastic features, including increased mitosis and reduced IKAROS expression, albeit without skewed T cell clonality. In summary, pharmacological inhibition of RORC not only blocks Th17 cell development and related cytokine production, but also recapitulates thymic aberrations seen in Rorc-deficient mice. While RORC inhibition may offer an effective therapeutic principle for Th17-mediated diseases, T cell lymphoma with chronic therapy remains an apparent risk.

Authors

Christine Guntermann, Alessandro Piaia, Marie-Laure Hamel, Diethilde Theil, Tina Rubic-Schneider, Alberto del Rio-Espinola, Linda Dong, Andreas Billich, Klemens Kaupmann, Janet Dawson, Klemens Hoegenauer, David Orain, Samuel Hintermann, Rowan Stringer, Dhavalkumar D. Patel, Arno Doelemeyer, Mark Deurinck, Jens Schümann

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Figure 2

Effects of retinoic-acid-orphan-receptor-C (RORC) inhibitors (cpd 1 and cpd 2) on T cells in vitro.

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Effects of retinoic-acid-orphan-receptor-C (RORC) inhibitors (cpd 1 and ...
RORC inhibitors (cpd 1 and cpd 2) specifically suppress human Th17 (A–B) or Tc17 cell polarization (C), while leaving Th0 (D), Th1 (E), or Th2 (F) signature cytokine production intact. Representative examples of concentration-response curves from 3 experiments with triplicate readings are shown. Total (A) or naive CD4+ (B) or CD8+ (C) T cells derived from blood of human healthy donors were stimulated with anti-CD3 and anti-CD28 antibodies in the presence of Th17-polarizing cytokines for 72 or 96 hours, and IL-17A production was quantified. Alternatively, CD4+ T cells were stimulated with anti-CD3/CD28 only (Th0) (D) and incubated with IL-12 and anti–IL-4 antibody (Th1) (E), or with IL-4 and anti–IFN-γ antibody (Th2) (F). IL-2, IFN-γ, and IL-13 cytokine production by the respective Th subsets was analyzed by ELISA after 48 hours. (G) Human CD4+ T cells were activated under Th17-, Th0-, Th1-, or Th2-polarizing conditions in the presence of RORC inhibitors or DMSO. Production of IL-17A, IL-2, IFN-γ, or IL-4 was analyzed by intracellular staining and flow cytometry. Intracellular cytokines within CD4+ T cell blasts are shown. Data are representative of 2 independent experiments. (H) Human γδ T cells were incubated with RORC inhibitors or DMSO only (Co) and stimulated with PMA/ionomycin for 24 hours. IL17A transcript levels were quantified by RT-PCR. Gene expression was normalized to β-glucuronidase levels and is expressed as arbitrary units. Results are representative of 2 independent experiments. Individual data and mean ± SD from triplicate readings are depicted. (I) CD4+ T cells isolated from splenocytes from male Lewis rats were stimulated with anti-CD3 and anti-CD28 antibodies in the presence of Th17-polarizing cytokines. IL-17A concentrations in supernatants were determined by ELISA. Representative examples of concentration-response curves from 3 experiments with triplicate readings are shown.

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