Abstract
Tertiary lymphoid structures are clusters of lymphoid tissue that develop post-natally at sites of chronic inflammation. They have been described in association with infection, autoimmune disorders, cancer, and allograft rejection. In their mature stage, TLS function as ectopic germinal centers, favoring the local production of autoantibodies and cytokines. TLS formation tends to parallel the severity of tissue injury and they are usually indicative of locally active immune responses. The presence of TLS in patients with solid tumors is usually associated with a better prognosis whereas their presence predicts increased maladaptive immunologic activity in patients with autoimmune disorders or allograft transplantation. Recent data highlight a correlation between active cell death and TLS formation and maturation. Our group recently identified apoptotic exosome-like vesicles, released by apoptotic cells, as novel inducers of TLS formation. Here, we review mechanisms of TLS formation and maturation with a specific focus on the emerging importance of tissue injury, programmed cell death and extracellular vesicles in TLS biogenesis.
Highlights
Tertiary lymphoid structures (TLS) are ectopic aggregates of lymphocytes and stromal cells, which, at maturity, behave as functional sites of adaptive immune responses [1, 2]
TLS display different organization levels ranging from simple clusters of B and T lymphocytes to more mature structures where T and B cells are polarized and follicular dendritic cells (FDCs) expressing CD21 and p75 neurotrophin receptor are present, allowing the formation of germinal centers (GC) [1, 5,6,7]
Induced pulmonary infection in neonatal mice, ab and gd T cells were detected within Inducible Bronchus-Associated Lymphoid Tissues. gd T cells formed a large proportion of infiltrating cells and both contributed to IL-17 production. Adoptive transfer of these purified T cell subsets, separately or together, to LPStreated Tcrbd-/- neonatal mice, showed preferential contribution of gd T cells in promoting iBALT development and of ab T cells in forming larger areas of iBALT [83]. Using another model of pulmonary infection induced by Pseudomonas aeruginosa, gd T cells were found to be the main source of IL-17 within iBALT, inducing CXCL-12 production by IL-17R+ stromal cells, B cell recruitment and follicles formation independent of FDC
Summary
Tertiary lymphoid structures (TLS) are ectopic aggregates of lymphocytes and stromal cells, which, at maturity, behave as functional sites of adaptive immune responses [1, 2]. In contrast to secondary lymphoid organs (SLO) (such as spleen, lymph nodes and Peyer’s patches), TLS are nonencapsulated and form postnatally. They exhibit plasticity and their presence is transient, correlating with active tissue injury and resolving after antigenic clearance and tissue repair [3]. They are composed of T and B cells as well as stromal cells, such as follicular dendritic cells (FDCs) and aSMA+ fibroblasts.
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