In this study we show for the first time that the quintessential Th17 transcription-factor, STAT3, collaborates with Class-O Forkhead transcription-factors to confer survival advantages to Th17 phenotype by limiting excessive T cell proliferation through upregulation of Class O Forkhead transcription factors. In contrast to Th1 cells that transiently produce high amounts of IL-2, we show that Th17 cells constitutively produce lower levels of IL-2. By limiting IL-2 production to very low levels, the Th17 cells avoid provoking IL-2-induced activation-induced-cell-death while promoting Th17 homeostatic expansion. Low constitutive IL-2 expression also confers selective growth advantage in low IL-2 environment and this allows Th17 effector cells to survive and persist in peripheral tissues and promote chronic inflammation, such as uveitis. In addition, we found that STAT3 has wide-ranging functions in all T cells and that it is convergence point for mechanisms that regulate lymphocyte quiescence and those controlling T cell activation and survival. We also provide mechanistic insights into how STAT3 and Forkhead transcription-factors converge to exert global regulation on all lymphocyte subsets. Specifically we show that: (i) STAT3 inhibits T-cell proliferation by up-regulating expression of T-cell quiescence factors (FoxO1, FoxO3a, Foxj1) and p27Kip1;(ii) Although STAT3 functions mainly as a transcription-factor, we show that it inhibits expansion of T-helper cells through a novel transcription-independent mechanism whereby STAT3 interacted with FoxO1/Foxo3a in cytoplasm, induced their nuclear localization in response to IL-6-stimulation and curtailed IL-2 production by promoting IκB-mediated sequestration of NF-κB;(iii) STAT3 promoted lymphocyte survival by up-regulating anti-apoptotic Bcl-2 and OX40 while down-regulating pro-apoptotic proteins. In terms of broader biological significance, it is important to note that FoxO proteins are implicated in regulating lifespan of C. elegans. Thus similar to their role in worms, FoxO and STAT3 pathways converge to extend lifespan of lymphoid cells.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAEY000315-22
Application #
8737618
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
22
Fiscal Year
2013
Total Cost
$330,949
Indirect Cost
Name
U.S. National Eye Institute
Department
Type
DUNS #
City
State
Country
Zip Code
Wan, Chi-Keung; He, Chang; Sun, Lin et al. (2016) Cutting Edge: IL-1 Receptor Signaling is Critical for the Development of Autoimmune Uveitis. J Immunol 196:543-6
Egwuagu, C E; Sun, L; Kim, S-H et al. (2015) Ocular Inflammatory Diseases: Molecular Pathogenesis and Immunotherapy. Curr Mol Med 15:517-28
Kim, Sung-Hye; Burton, Jenna; Yu, Cheng-Rong et al. (2015) Dual Function of the IRF8 Transcription Factor in Autoimmune Uveitis: Loss of IRF8 in T Cells Exacerbates Uveitis, Whereas Irf8 Deletion in the Retina Confers Protection. J Immunol 195:1480-8
Sun, Lin; He, Chang; Nair, Lekha et al. (2015) Interleukin 12 (IL-12) family cytokines: Role in immune pathogenesis and treatment of CNS autoimmune disease. Cytokine 75:249-55
He, Chang; Yu, Cheng-Rong; Sun, Lin et al. (2015) Topical administration of a suppressor of cytokine signaling-1 (SOCS1) mimetic peptide inhibits ocular inflammation and mitigates ocular pathology during mouse uveitis. J Autoimmun 62:31-8
Yu, Cheng-Rong; Hayashi, Kozaburo; Lee, Yun Sang et al. (2015) Suppressor of cytokine signaling 1 (SOCS1) mitigates anterior uveitis and confers protection against ocular HSV-1 infection. Inflammation 38:555-65
Egwuagu, Charles E (2014) Chronic intraocular inflammation and development of retinal degenerative disease. Adv Exp Med Biol 801:417-25
Yu, Cheng-Rong; Dambuza, Ivy M; Lee, Yong-Jun et al. (2013) STAT3 regulates proliferation and survival of CD8+ T cells: enhances effector responses to HSV-1 infection, and inhibits IL-10+ regulatory CD8+ T cells in autoimmune uveitis. Mediators Inflamm 2013:359674
Egwuagu, Charles E; Larkin Iii, Joseph (2013) Therapeutic targeting of STAT pathways in CNS autoimmune diseases. JAKSTAT 2:e24134
Escobar, Thelma; Yu, Cheng-Rong; Muljo, Stefan A et al. (2013) STAT3 activates miR-155 in Th17 cells and acts in concert to promote experimental autoimmune uveitis. Invest Ophthalmol Vis Sci 54:4017-25

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