The disruption of FRC stromal architecture in immunized FRCdLN did not disrupt B and T cell zones, and frequencies of na?ve and effector T cell populations, as well as IL-17-producing TH17 cells, were unaffected (Fig. an important driver of inflamed LN stromal cell activation, through metabolic reprogramming required to support proliferation and survival. INTRODUCTION E3330 TH17 cells promote pathology in a variety of autoimmune conditions, and therapies targeting TH17 cells are proving highly effective in some autoimmune diseases1, 2. Interleukin 17 (IL-17), the prototypical TH17 cytokine, targets non-hematopoietic cells to induce production of chemokines that attract myeloid cells, pro-inflammatory cytokines such as IL-6, and antimicrobial peptides2. TH17 cells are therefore important regulators of extracellular bacterial and fungal pathogens. In the healthy skin and gut, IL-17 maintains microbial homeostasis without overt inflammation, and supports gut epithelial healing following toxic E3330 injury3, 4. IL-17 also promotes development of tertiary lymphoid structures that support protective immunity, but may perpetuate chronic inflammation during autoimmunity5, 6. Hence, the context of IL-17 signaling plays an important role in eliciting an inflammatory or tissue-protective response. Like all na?ve T cells, TH17 cells are activated and differentiate in secondary lymphoid organs (SLOs) including lymph E3330 nodes (LNs) and spleen, where they have an opportunity to interact with resident stromal cells during differentiation. Fibroblastic reticular cells (FRCs) are the critical non-hematopoietic stromal cells in SLOs. T cell zone FRCs were the first identified FRC population, characterized to express the chemokine CCL19 and IL-7 to attract T cells and support their survival7. They also secrete extracellular matrix (ECM) that ensheaths conduits carrying lymph for dendritic cell (DC) sampling, and forms a cellular scaffold that facilitates T cell migration7. In addition to T cell zone stroma, FRCs are now known to comprise heterogeneous subpopulations occupying distinct niches throughout the LN. Recent single-cell level analyses of LN stromal cells delineated seven podoplanin (PDPN)+ FRC subpopulations8. These subsets include follicular dendritic cells (FDCs) in B cell follicles, marginal zone reticular cells (MRCs) in the subcapsullar sinus, 2 populations of medullary reticular cells (MedRCs) known to support plasma cells9, and 3 subsets of T zone reticular cells (TRCs): classical CCL19hi TRCs, a CXCL9+ interfollicular TRC population, and a CCL19lo TRC population that expresses the B cell survival factor BAFF and the B cell-attracting chemokine CXCL13 at B:T zone borders10. FRC depletion or dysfunction in mouse models causes SLO follicular disorganization, reduced T and B cell viability, and impaired antiviral immunity10,11,. Chronic fibrosis of LNs that occurs during HIV or SIV infection exacerbates T cell loss due to reduced access to IL-7 from FRCs coated in excess ECM12, 13. Similar LN fibrosis with reduced FRC numbers was found in subjects from Uganda with chronic immune activation syndrome, corresponding to reduced T cells and impaired antibody production following vaccination14. Conversely, FRCs regulate the magnitude of type 1 CD4+ T helper (TH1) and CD8+ T cell responses through Rabbit Polyclonal to BCL2 (phospho-Ser70) production of nitric oxide in response to interferon- (IFN-)15, 16, 17. Similarly, FRCs regulate type 1 innate lymphoid cell (ILC1) responses by reducing IL-15 production in response to MyD88 signaling18. Thus FRCs are thought to reduce immunopathology during viral infection. By presenting self antigens, FRCs can delete self-reactive CD8+ T cells and induce CD4+ regulatory T (Treg) cells 19, 20. Hence FRCs play important roles both in supporting and regulating adaptive immune responses. Following pathogen invasion or immunization, activated DCs migrate to local LNs and trigger endothelial shutdown, generating rapid organ size increase due to retained lymphocytes21. At first, cytoskeletal relaxation in FRC allows stretching of the network22. Then, FRCs proliferate to provide the increased stromal support needed by the expanded lymphoid tissue23, 24. The kinetics of FRC proliferation are offset against LN size increase by several days24 and more closely follow activation kinetics of T cells, which are thought to provide proliferation-supporting signals24, 25. However, the nature of these signals have been unclear. In this study, we investigated the role of IL-17 produced by differentiating TH17 cells on local FRCs during inflammation in SLOs. RESULTS TH17 cells drive increased ECM in inflamed LNs Increased production of ECM components such as fibronectin and collagen are features of TH17-mediated inflammation, including the central nervous system (CNS) during multiple sclerosis (MS) or its animal model experimental autoimmune encephalomyelitis (EAE)26, 27. Following immunization with the myelin oligodendrocyte glycoprotein peptide MOG(aa35C55) in complete Freunds adjuvant (CFA) to induce EAE, we observed that expression of (encoding.