IL-17 regulates LN stromal cell metabolism and function

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ABSTRACT Th17 cells promote pathology in a variety of autoimmune conditions, and new therapies targeting Th17 cells or IL-17 are proving highly effective. In the healthy state, Th17 cells maintain microbial homeostasis in mucosal sites and are important regulators of extracellular bacterial and fungal pathogens 3. Th17 cells are generated in secondary lymphoid organs (SLO), but their primary effects are usually assessed in peripheral target tissues related to clinical disease manifestations. In SLO, specialized stromal cells called fibroblastic reticular cells (FRC) provide structural support to lymphocytes, including establishment of organized functional cellular niches through production of chemokines and pro-survival cytokines. A less well-appreciated role of FRC is to modulate the adaptive immune response. FRC are required for effective anti-viral responses including antibody (Ab) production, but in turn limit Th1 and CD8 T cell proliferation in response to IFNγ produced by T cells. However, Th17:FRC interactions remain almost entirely unexplored. We now show that IL-17 plays a critical role in expansion and survival of FRC in two distinct model settings: experimental autoimmune encephalomyelitis (EAE) and colitis. Unexpectedly, IL-17 induced metabolic reprogramming of activated FRC and we identified IκBζ as a critical transcriptional coactivator of IL-17-mediated metabolic effects in vitro. Our data furthermore show that IL-17 activation of FRC enhances adaptive immunity: Conditional deletion of IL- 17R on CCL19+FRC resulted in impaired B cell germinal center formation and antibody production. These data inform our central hypothesis that during Th17 inflammation, IL-17 signaling drives successful metabolic reprogramming and expansion of FRC which allows fulminant activation of the adaptive immune response. In this application we propose interrogating the mechanisms by which IL-17 activates the FRC response and the consequent impact on adaptive immunity. More broadly, by using FRC as a model system to interrogate the IL- 17-IκBζ-metabolism pathway and impact on adaptive immunity, we will gain mechanistic insights on known but still poorly-understood functions of IL-17 in autoimmune inflammation, barrier maintenance, infection resistance and wound healing. This knowledge is important to guide future therapeutic strategies based on reducing harmful effects of IL-17 while maintaining beneficial functions. !