Fibroblastic reticular cells initiate immune responses in visceral adipose tissues and secure peritoneal immunity

Abstract

Immune protection of the body cavities depends on the swift activation of innate and adaptive immune responses in nonclassical secondary lymphoid organs known as fat-associated lymphoid clusters (FALCs). Compared with classical secondary lymphoid organs such as lymph nodes and Peyer's patches, FALCs develop along distinct differentiation trajectories and display a reduced structural complexity. Although it is well established that fibroblastic reticular cells (FRCs) are an integral component of the immune-stimulating infrastructure of classical secondary lymphoid organs, the role of FRCs in FALC-dependent peritoneal immunity remains unclear. Using FRC-specific gene targeting, we found that FRCs play an essential role in FALC-driven immune responses. Specifically, we report that initiation of peritoneal immunity was governed through FRC activation in a myeloid differentiation primary response 88 (MYD88)-dependent manner. FRC-specific ablation of MYD88 blocked recruitment of inflammatory monocytes into FALCs and subsequent CD4 T cell-dependent B-cell activation and IgG class switching. Moreover, containment of infection was compromised in mice lacking MYD88 expression in FRCs, indicating that FRCs in FALCs function as an initial checkpoint in the orchestration of protective immune responses in the peritoneal cavity.

TLR9 signaling in fibroblastic reticular cells regulates peritoneal immunity

“…Fibroblastic reticular cells (FRCs), characterized as CD45 -, CD31 -, and podoplanin + (PDPN + ), are a unique subpopulation of stromal cells in lymphoid organs, such as lymph nodes and fatassociated lymphoid clusters (FALCs) (7,8). FRCs are essential for the formation of lymphoid organs, as they fashion the scaffolding that recruits and supports immune cells (9)(10)(11)(12)(13)(14)(15)(16). Besides their structural functions, FRCs have been recognized as major regulators of both innate and adaptive immunity in response to microbial pathogen invasion through interactions with neighboring immune cells within lymphoid tissues (9,10,14,17).…”

SIRPα+ dendritic cells promote the development of fibroblastic reticular cells in murine peripheral lymph nodes

“…By contrast, we previously found that the absolute number of T cells, as well as that of FRCs, in pLNs did not differ between Sirpa ΔDC and Sirpa f/f mice, suggesting that SIRPα + DCs are dispensable for the homeostasis of FRCs in pLNs under the steady‐state condition . Given that the TNF‐mediated activation of FRCs in vitro culture and renal subcapsular transplant models mimic the development or remodeling of pLNs, SIRPα + DCs are likely important for regeneration of FRCs in secondary lymphoid organs during immune responses or viral infection , as well as for TNF‐mediated activation of FRCs and the attraction of myeloid cells by CCL2 in nonclassical lymphoid organs after Salmonella infection , rather than for their maintenance under the steady‐state condition.…”

Neutrophils mediate the capture of peritoneal contaminants by fat-associated lymphoid clusters of the omentum

“…The final cluster of fibroblasts (purple) was characterised by the expression of Ccl19. The existence of a dense network of PDFGRα + fibroblast reticular cells (FRC) expressing Ccl19 and embedding FALC B cells was recently described in the omentum and mesenteries (Perez-Shibayama et al, 2018). This cluster showed enrichment for genes involved in formation of the extra-cellular matrix (ECM) characteristic of lymph node (LN) and FALC FRCs such as Sparcl,Matn2,Spon2,Col15a1,Bgn,Emilin1 and Spon1 (Fig.…”

“…1D,I and Supplementary Fig. 1E) (Huang et al, 2018;Malhotra et al, 2012;Perez-Shibayama et al, 2018). We thus assigned this cluster the name Ccl19 + Pdgfra + FALC FRCs.…”

“…Peritonitis induces de novo FALC formation, which is dependent on the production of TNF by monocyte/macrophages and TNFR-signalling in stromal cells (Benezech et al, 2015). The initial recruitment of inflammatory monocytes into FALCs is dependent on MYD88 dependent activation of Ccl19 expressing FALC stromal cells (Perez-Shibayama et al, 2018). The cross-talk between monocyte/macrophage and FALC stromal cells is required to support B cell differentiation (Perez-Shibayama et al, 2018) and FALC expansion (Benezech et al, 2015).…”