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Isolation and Th17 Differentiation of Naïve CD4 T Lymphocytes
Published on: September 26, 2013
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IL-23R-activated STAT3/STAT4 is essential for Th1/Th17-mediated CNS autoimmunity
Priscilla W Lee1,2, Alan J Smith3, Yuhong Yang4
1Department of Microbial Infection and Immunity.
JCI Insight
|September 8, 2017
Summary
Cytokines IL-6 and IL-12 induce IL-23 receptor expression, driving pathogenic T cell differentiation in CNS autoimmunity. STAT4 signaling is crucial for this process, impacting autoimmune disease development.
Area of Science:
- Immunology
- Neuroimmunology
- Autoimmunity
Background:
- Factors driving pathogenic T cell differentiation in autoimmune diseases remain unclear.
- Previous studies using genetically modified mice yielded contradictory findings on molecules involved in autoimmunity.
- Understanding minimal signals for encephalitogenic T cell development is critical for CNS autoimmunity research.
Purpose of the Study:
- To define the minimum cytokine signals required for the development of encephalitogenic T cells.
- To investigate the role of IL-23 signaling and its downstream effectors (STAT3, STAT4) in CNS autoimmunity.
- To correlate findings in mouse models with human T cells from multiple sclerosis patients.
Main Methods:
- Differentiating myelin-specific T cells with various cytokine cocktails (IL-6+IL-23, IL-12+IL-23).
- Assessing pathogenicity by transferring differentiated T cells into recipient mice.
- Analyzing STAT3 and STAT4 signaling pathways, including receptor expression and phosphorylation.
- Examining CD4+ memory T cells from multiple sclerosis patients for STAT3/STAT4 activation.
Main Results:
- IL-6+IL-23 and IL-12+IL-23 cytokine combinations generated encephalitogenic T cells.
- Both IL-6 and IL-12 induced IL-23 receptor expression on naive T cells (mouse and human).
- IL-23 signaling involved both STAT3 and STAT4; STAT4 disruption impaired CNS autoimmunity independently of IL-12.
- STAT4-deficient mice were resistant to CNS autoimmunity, unlike IL-12-deficient mice.
- Multiple sclerosis patient T cells showed elevated p-STAT3/p-STAT4 levels, with heterodimers upon IL-23 signaling.
Conclusions:
- IL-23 signaling via STAT3 and STAT4 orchestrates pathogenic T cell generation in CNS autoimmunity.
- This mechanism operates irrespective of the Th1 or Th17 T cell phenotype.
- Findings explain differential susceptibility in IL-12 and STAT4 deficient models.
- Targeting IL-23/STAT4 pathways may offer therapeutic strategies for CNS autoimmune diseases.
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