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.
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