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IL-23R–activated STAT3/STAT4 is essential for Th1/Th17-mediated CNS autoimmunity
Priscilla W. Lee, … , Michael K. Racke, Amy E. Lovett-Racke
Priscilla W. Lee, … , Michael K. Racke, Amy E. Lovett-Racke
Published September 7, 2017
Citation Information: JCI Insight. 2017;2(17):e91663. https://doi.org/10.1172/jci.insight.91663.
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Research Article Immunology

IL-23R–activated STAT3/STAT4 is essential for Th1/Th17-mediated CNS autoimmunity

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Abstract

The factors that promote the differentiation of pathogenic T cells in autoimmune diseases are poorly defined. Use of genetically modified mice has provided insight into molecules necessary for the development of autoimmunity, but the sum of the data has led to contradictory observations based on what is currently known about specific molecules in specific signaling pathways. To define the minimum signals required for development of encephalitogenic T cells that cause CNS autoimmunity, myelin-specific T cells were differentiated with various cytokine cocktails, and pathogenicity was determined by transfer into mice. IL-6+IL-23 or IL-12+IL-23 generated encephalitogenic T cells and recapitulated the essential cytokine signals provided by antigen-presenting cells, and both IL-6 and IL-12 induced IL-23 receptor expression on both mouse and human naive T cells. IL-23 signaled through both STAT3 and STAT4, and disruption in STAT4 signaling impaired CNS autoimmunity independent of IL-12. These data explain why IL-12–deficient mice develop CNS autoimmunity, while STAT4-deficient mice are resistant. CD4+ memory T cells from multiple sclerosis patients had significantly higher levels of p-STAT3/p-STAT4, and p-STAT3/p-STAT4 heterodimers were observed upon IL-23 signaling, suggesting that p-STAT3/p-STAT4 induced by IL-23 signaling orchestrate the generation of pathogenic T cells in CNS autoimmunity, regardless of Th1 or Th17 phenotype.

Authors

Priscilla W. Lee, Alan J. Smith, Yuhong Yang, Amanda J. Selhorst, Yue Liu, Michael K. Racke, Amy E. Lovett-Racke

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Figure 7

IL-23 induces higher phosphorylation levels of STAT3 and STAT4 in memory CD4+ T cells from MS patients.

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IL-23 induces higher phosphorylation levels of STAT3 and STAT4 in memory...
PBMCs from healthy individuals (n = 7) and treatment-naive MS (n = 8) patients were activated in vitro with anti-CD3 for 2 days. The cells were washed and rested in fresh medium for 4 hours and then were stimulated with either IL-23 or PBS for 20 minutes. Phosphorylation of STAT3 and STAT4 in memory CD4+ T cells was analyzed by flow cytometry. Memory CD4+ T cells were gated on CD3+CD8–CD45RA– populations. (A) Three representative samples from healthy individuals and MS patients are shown. HI, healthy individuals. (B) The percentage of p-STAT4 single-positive, p-STAT3 single-positive, and p-STAT3/p-STAT4 double-positive subpopulations in memory CD4+ T cells from healthy individuals and MS patients are shown. *P < 0.05, **P < 0.01 (1-way ANOVA with Bonferroni’s multiple comparison test). (C) Memory CD4+ T cells were purified from PBMCs of healthy individuals (n = 8) and treatment-naive MS patients (n = 16). The purified cells were stimulated with PMA/ionomycin for 4 hours. IL23R and HPRT mRNA were detected by real-time PCR. Results were normalized with HPRT. Fold change was calculated relative to the average of healthy individuals group (mean ± SEM) using unpaired Student’s t test. (D) The degree of relatedness between the level of IL23R expression and percentage of p-STAT3+ or p-STAT3+/p-STAT4+ cells of the same donor (n = 6) was analyzed by nonparametric Pearson correlation test.

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