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Review
. 2016 Nov 8:7:477.
doi: 10.3389/fimmu.2016.00477. eCollection 2016.

Stromal Fibroblasts in Tertiary Lymphoid Structures: A Novel Target in Chronic Inflammation

Francesca Barone  1 , David H Gardner  1 , Saba Nayar  1 , Nathalie Steinthal  1 , Christopher D Buckley  1 , Sanjiv A Luther  2
Affiliations
Review

Stromal Fibroblasts in Tertiary Lymphoid Structures: A Novel Target in Chronic Inflammation

Francesca Barone et al. Front Immunol. .

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.

Keywords: beta2 heterotrimer; chemokines; fibroblasts; lymphotoxin alpha1; tertiary lymphoid structures; tumor necrosis factor-alpha.

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Figures

Figure 1
Figure 1
Development and maturation of lymphoid tissue-like stromal fibroblasts in tertiary lymphoid structure (TLS). Multistep model illustrating the priming followed by the stabilization and maturation of the fibroblasts allowing a lymphoid tissue-like organization and function of the lymphocyte infiltrate. Acute inflammation within a tissue results in the localized production of several different proinflammatory cytokines by infiltrating leukocyte populations (initiators) and tissue-resident cells. These signals elicit “priming” of local stromal fibroblasts, which may include the upregulation of gp38, adhesion molecules, and inflammatory cytokines. Prolonged inflammation can lead to local production of LTα1β2, along with TNFα and LTα by hematopoietic inducer cells. This triggers changes in the stromal fibroblast phenotype and function, including the production of chemokines typically expressed in lymphoid organs. FDC differentiation from local fibroblasts might only occur at this stage, when a critical mass of LTα3/LTα1β2/TNFα signals are provided by the co-localizing B cells, possibly inducing a positive feedback loop. Organization of the resident stroma and hematopoietic cells in a T cell (blue cells) and B cell (green cells) rich zone enables priming and activation of T and B cells toward locally displayed antigens. The formation of GC supports affinity maturation and expansion of B cells clones and plasma cells. Not Illustrated: the presence and differentiation of the vascular network [reviewed in Ref. (57)].
Figure 2
Figure 2
Stromal fibroblast populations in SLO and TLS. (A) Fibroblast populations in the lymph node control the organization and survival of lymphocytes in distinct areas. Fibroblastic reticular cells (FRC) produce CCL19 and CCL21 along with the survival factor IL-7 to attract and maintain T cell populations and provide a niche in which their interaction with dendritic cells (DC) can occur. Follicular dendritic cells (FDC) produce CXCL13, which attracts CXCR5+ cells to the B cell follicles. Other stromal cells are thought to play a role during the germinal center reaction (i.e., CRCs) or in antigen delivery (MRC). (B) Mature TLS are characterized by segregation into distinct T cell and B cell areas including the presence of germinal center like structures and areas rich in plasma cells. Stromal cell populations that perform comparable functions to those found within SLO can be identified, which underlie this T/B cell segregation within the larger TLS.
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