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Significance TLS, which are clusters of lymphocytes and stromal cells observed at sites of chronic inflammation, play a key role in sustaining disease progression in autoimmune conditions. While the role of lymphocytes in these structures has been studied extensively, the role of fibroblasts, nonhematopoietic stromal cells, in the formation and maintenance of TLS has not been demonstrated. Here, we establish that, at sites of TLS establishment, resident fibroblasts expand and acquire immunological features in a process that is dependent on IL13 and IL22. Interference with this process or depletion of immunofibroblasts leads to involution of TLS, resulting in decreased immune-cell activation and resolution of tissue pathology, thus supporting the use of fibroblast-targeting strategies to treat TLS-associated autoimmune diseases., Resident fibroblasts at sites of infection, chronic inflammation, or cancer undergo phenotypic and functional changes to support leukocyte migration and, in some cases, aggregation into tertiary lymphoid structures (TLS). The molecular programming that shapes these changes and the functional requirements of this population in TLS development are unclear. Here, we demonstrate that external triggers at mucosal sites are able to induce the progressive differentiation of a population of podoplanin (pdpn)-positive stromal cells into a network of immunofibroblasts that are able to support the earliest phases of TLS establishment. This program of events, that precedes lymphocyte infiltration in the tissue, is mediated by paracrine and autocrine signals mainly regulated by IL13. This initial fibroblast network is expanded and stabilized, once lymphocytes are recruited, by the local production of the cytokines IL22 and lymphotoxin. Interfering with this regulated program of events or depleting the immunofibroblasts in vivo results in abrogation of local pathology, demonstrating the functional role of immunofibroblasts in supporting TLS maintenance in the tissue and suggesting novel therapeutic targets in TLS-associated diseases.

The molecular mediators present within the inflammatory microenvironment are able, in certain conditions, to favor the initiation of tertiary lymphoid structure (TLS) development. TLS is organized lymphocyte clusters able to support antigen-specific immune response in non-immune organs. Importantly, chronic inflammation does not always result in TLS formation; instead, TLS has been observed to develop specifically in permissive organs, suggesting the presence of tissue-specific cues that are able to imprint the immune responses and form TLS hubs. Fibroblasts are tissue-resident cells that define the anatomy and function of a specific tissue. Fibroblast plasticity and specialization in inflammatory conditions have recently been unraveled in both immune and non-immune organs revealing a critical role for these structural cells in human physiology. Here, we describe the role of fibroblasts in the context of TLS formation and its functional maintenance in the tissue, highlighting their potential role as therapeutic disease targets in TLS-associated diseases.

Primary SS (pSS) is a chronic autoimmune condition characterized by infiltration of the exocrine glands and systemic B cell hyperactivation. This glandular infiltration is associated with loss of glandular function, with pSS patients primarily presenting with severe dryness of the eyes and mouth. Within the affected glands, the infiltrating lymphocytes are organized in tertiary lymphoid structures. Tertiary lymphoid structures subvert normal tissue architecture and impact on organ function, by promoting the activation and maintenance of autoreactive lymphocytes. This review summarizes the current knowledge about the role of stromal cells (including endothelium, epithelium, nerves and fibroblasts) in the pathogenesis of pSS, in particular the interactions taking place between stromal cells and infiltrating lymphocytes. We will provide evidences pointing towards the driving role of stromal cells in the orchestration of the local inflammatory milieu, thus highlighting the need for therapies aimed at targeting this compartment alongside classical immunosuppression in pSS.