Abstract
Tertiary lymphoid structures (TLS) are organized aggregates of lymphocytes, myeloid, and stromal cells that provide ectopic hubs for acquired immune responses. TLS share phenotypical and functional features with secondary lymphoid organs (SLO); however, they require persistent inflammatory signals to arise and are often observed at target sites of autoimmune disease, chronic infection, cancer, and organ transplantation. Over the past 10 years, important progress has been made in our understanding of the role of stromal fibroblasts in SLO development, organization, and function. A complex and stereotyped series of events regulate fibroblast differentiation from embryonic life in SLOs to lymphoid organ architecture observed in adults. In contrast, TLS-associated fibroblasts differentiate from postnatal, locally activated mesenchyme, predominantly in settings of inflammation and persistent antigen presentation. Therefore, there are critical differences in the cellular and molecular requirements that regulate SLO versus TLS development that ultimately impact on stromal and hematopoietic cell function. These differences may contribute to the pathogenic nature of TLS in the context of chronic inflammation and malignant transformation and offer a window of opportunity for therapeutic interventions in TLS associated pathologies.
Highlights
Organs are defined as collection of cells, extracellular structures, and fluids, joined into an operational unit to serve a common function
In secondary lymphoid organs (SLO), this first phase is followed by the LTα1β2-dependent interaction of lymphoid tissue inducer (LTi) cells with the primed mesenchymal cells leading to their specialization as lymphoid tissue organizer cell (LTo) cells capable of inducing high endothelial venules (HEVs) development, lymphocyte recruitment, and stromal cell specialization in various subsets [28, 29, 135]
While this review focuses on fibroblasts, the ability of hematopoietic cells, including macrophages, dendritic cells, and Th17 cells, to ectopically express CXCL13 should be acknowledged, suggesting the possibility to consider the cytokine/chemokine, rather than its cellular origin as a therapeutic target [148,149,150,151,152]
Summary
Organs are defined as collection of cells, extracellular structures, and fluids, joined into an operational unit to serve a common function. SLOs hold a network of fibroblasts, vessels, and nerves that support a large mobile population of leukocyte and which support immune surveillance and response to noxious agents [1, 2] This elegant organization of SLOs develops in a highly conserved and regulated process that largely occurs, both in mice and humans, in embryonic and early postnatal life [3, 4]. Fibroblast phenotype and function greatly differ between various anatomical sites, as shown by the extensive transcriptional differences detected in fibroblasts isolated from different compartments in diverse locations of the body [17] This specialization is further enhanced by the specific ability of fibroblasts to respond to a series of cytokines and inflammatory stimuli, which increase their proliferative capacity and induce functional adaptations to the environment [18,19,20,21,22]. This review will focus on a subset of fibroblasts defined as “lymphoid tissue fibroblasts,” which inhabit SLOs and TLS, are characterized by extensive plasticity and specialized functions, and have recently emerged as important regulators of adaptive immunity [8, 23,24,25]
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