Role of Fibroblast-Immune Crosstalk in Kidney, Lung, and Skin Tertiary Lymphoid Structures

Tertiary lymphoid structures (TLSs) are organized aggregates of lymphocytes, myeloid cells, and stromal cells that form at sites of inflammation, providing adaptive immune responses outside of secondary lymphoid organs (SLOs). Found in various pathological conditions—including chronic infections, cancer, organ transplantation, autoimmune diseases, and allergy—the presence of TLSs is linked to potentiation of local immunity. TLSs can be beneficial or detrimental, depending on context, and have been implicated as prognostic for disease severity and therapy response. Architecturally, TLSs resemble SLOs with distinct T and B cell areas supported by fibroblasts that secrete chemokines and cytokines that support immune cells. These structures must be created de novo in non-lymphoid tissues; thus, the steps for TLS formation mimic, but do not completely copy, those of SLO formation. The accumulation of immune cells in tissues in inflammatory settings can initiate remodeling of tissue fibroblasts, leading to TLS formation; this process is common across tissues, although there are tissue- and disease-specific pathways that impact TLS formation in certain contexts. This review will explore the immune-stromal crosstalk in kidney, lung, and skin TLSs across a range of disease settings, highlighting shared as well as tissue-specific mechanisms for TLS formation.