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Updated: May 11, 2026
Isolation and Th17 Differentiation of Naïve CD4 T Lymphocytes
Published on: September 26, 2013
STAT3 activates miR-155 in Th17 cells and acts in concert to promote experimental autoimmune uveitis
Thelma Escobar1, Cheng-Rong Yu, Stefan A Muljo
1Laboratory of Immunology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Bethesda, Maryland 20892, USA.
Purpose:
MicroRNA-155 (miR-155) and STAT3 are implicated in uveitis and pathogenic mechanisms of CNS autoimmune diseases. In our study, we used miR-155(-/-) mice and mice with targeted STAT3 deletion in T cells (CD4-STAT3KO) to investigate roles of miR-155 and STAT3 in the development of experimental autoimmune uveitis (EAU), a mouse model of human uveitis.
Methods:
We induced EAU in WT, miR-155(-/-), or CD4-STAT3KO mice by immunization with interphotoreceptor retinoid-binding protein/complete Freund's adjuvant (IRBP/CFA) or adoptive transfer of T cells. EAU was assessed by funduscopy and histology. RNA expression was analyzed by quantitative PCR (qPCR), while cytokine production was assessed by fluorescence-activated cell sorting (FACS).
Results:
We used a combination of genomic and genetic tools to provide the first evidence that STAT3 binds directly to the miR-155 locus and that STAT3 is required for miR-155 expression. Furthermore, STAT3-dependent increase in miR-155 expression in vivo correlated temporally with onset of EAU, and miR-155(-/-) or CD4-STAT3KO mice did not suffer EAU. CD4(+) lymph node cells from IRBP-immunized WT mice transferred EAU to naïve wild-type (WT) and miR-155(-/-) mice, while miR-155(-/-) IRBP-specific T cells did not.
Conclusions:
Although miR-155 and STAT3 have been implicated in the etiology of multiple sclerosis (MS), uveitis, or rheumatoid arthritis, their exact roles in these diseases are unclear. We show here for the first time to our knowledge that STAT3 regulates miR-155 expression in Th17 cells. We show further that STAT3 and miR-155 form an axis that promotes the expansion of pathogenic Th17 cells that mediate uveitis. Thus, STAT3 and miR-155 may be therapeutic targets for treating uveitis and other Th17-mediated inflammatory disorders.
Insights
STAT3 directly regulates microRNA-155 (miR-155) expression, which is crucial for developing experimental autoimmune uveitis (EAU). Mice lacking STAT3 in T cells or miR-155 were protected from EAU, suggesting a therapeutic target axis.
Area of Science:
- Immunology
- Ophthalmology
- Molecular Biology
Background:
- MicroRNA-155 (miR-155) and STAT3 are implicated in autoimmune diseases affecting the central nervous system and eyes.
- The precise roles of miR-155 and STAT3 in the pathogenesis of uveitis remain unclear.
Purpose of the Study:
- To investigate the roles of miR-155 and STAT3 in the development of experimental autoimmune uveitis (EAU).
- To elucidate the regulatory relationship between STAT3 and miR-155 in T cells.
Main Methods:
- Experimental autoimmune uveitis (EAU) was induced in wild-type (WT), miR-155 knockout (miR-155(-/-)), and CD4-STAT3 knockout (CD4-STAT3KO) mice.
- Assessment of EAU involved funduscopy and histology, with gene expression analyzed by quantitative PCR (qPCR) and cytokine production by fluorescence-activated cell sorting (FACS).
Main Results:
- STAT3 directly binds to the miR-155 locus and is required for its expression.
- STAT3-dependent miR-155 upregulation correlated with EAU onset; miR-155(-/-) and CD4-STAT3KO mice were protected from EAU.
- Adoptive transfer of T cells demonstrated that miR-155(-/-) T cells did not transfer EAU, unlike WT T cells.
Conclusions:
- STAT3 regulates miR-155 expression in Th17 cells, forming an axis that promotes pathogenic Th17 cell expansion.
- This STAT3-miR-155 axis is critical for mediating uveitis.
- STAT3 and miR-155 represent potential therapeutic targets for uveitis and other Th17-mediated inflammatory disorders.
