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C. E. Egwuagu, X. Liu, Y. Lee, P. Silver, R. Caspi, I. Gery, C.-R. Yu; Targeted Deletion of STAT3 in CD4+ T Cells Prevents Development of Experimental Autoimmune Uveoretinitis (EAU) and Recruitment of Pathogenic ThIL17 and Th1 Cells into the Retina. Invest. Ophthalmol. Vis. Sci. 2007;48(13):1098.
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ThIL17 cells have been implicated in etiology of multiple sclerosis, inflammatory bowel disease and rheumatoid arthritis. Recent reports have emphasized essential roles of IL-6 & TGFß1 in polarization of naive CD4+ cells into ThIL17 lineage and a requirement of STAT3 for IL-17 expression. However, IL-6 is also a potent activator of STAT3, suggesting that STAT3 may also regulate development and pathogenic mechanisms of ThIL17 cells. In this study we have examined whether ThIL17 cells are involved in pathogenic mechanisms of experimental autoimmune uveoretinitis (EAU) and used a mouse with targeted deletion of STAT3 in CD4+ cells to investigate the role of STAT3 in ThIL17 lineage commitment and in uveitis.
Mice with targeted deletion of STAT3 in the CD4+ T cell compartment (STAT3 conditional KO) were generated by mating STAT3fl/fl with CD4+-Cre mice. IRBP-induced EAU was characterized by histology, proliferation and DTH assays. Expression of transcription factors, lymphocyte effector molecules and cytokine secretion were assessed by Western blotting, RT-PCR, qRT-PCR or ELISA. Phenotype of lymph node or ocular pathogenic T-cells was analyzed by FACS and intracellular staining.
In contrast to wild type mice (WT), STAT3 conditional KO mice do not develop EAU. EAU in WT mice is characterized by infiltration of ThIL17 and Th1 cells into the retina and the pathogenic T cells express high levels of VLA-4 and LFA-1 integrins. In contrast, naive STAT3 conditional KO T cells fail to differentiate into ThIL17 phenotype, express low levels of VLA-4/LFA-1 integrins and do not enter the eye. Moreover, TGFß and IL-6 or IL-23 are unable to induce naive STAT3-deficient CD4 cells to differentiate into ThIL17 cells.
Accumulation of ThIL17/Th1 cells in the retina of mice with EAU suggests that both T cell subsets may be involved in pathogenic mechanisms of EAU. Our data showing for the first time that TGFß and IL-6 or IL-23 are unable to induce naive STAT3-deficient CD4 cells to differentiate into ThIL17 cells provides direct and compelling evidence that STAT3 regulates commitment of T cells into the ThIL17 lineage. Our data showing that IRBP-primed STAT3-deficient T cells do not enter the eye and that STAT3 regulates expression of integrin receptors that guide activated effector T cells to leave blood and enter the CNS/retina, suggest that STAT3 maybe a target for therapeutic modulation of uveitis.
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