Protective fibroblastic niches in secondary lymphoid organs

Abstract

Fibroblastic reticular cells (FRCs) are specialized fibroblasts of secondary lymphoid organs that provide the structural foundation of the tissue. Moreover, FRCs guide immune cells to dedicated microenvironmental niches where they provide lymphocytes and myeloid cells with homeostatic growth and differentiation factors. Inflammatory processes, including infection with pathogens, induce rapid morphological and functional adaptations that are critical for the priming and regulation of protective immune responses. However, adverse FRC reprogramming can promote immunopathological tissue damage during infection and autoimmune conditions and subvert antitumor immune responses. Here, we review recent findings on molecular pathways that regulate FRC-immune cell crosstalk in specialized niches during the generation of protective immune responses in the course of pathogen encounters. In addition, we discuss how FRCs integrate immune cell-derived signals to ensure protective immunity during infection and how therapies for inflammatory diseases and cancer can be developed through improved understanding of FRC-immune cell interactions.

Figure 1.

FRC subsets in murine and human SLOs. Schematic representation and marker annotation of FRC subsets in relation to the antigen sampling zones, T and B cell zones, and perivascular zones. Cxcl13-expressing BRCs include MRCs, FDCs, TBRCs, IFRCs, and BCRCs. MRCs underlie the subcapsular sinus (lymph node), the marginal sinus bordering red pulp, and B cell follicles (spleen) or the subepithelial dome (Peyer’s patch). In the human spleen, MRCs underlie the marginal zone and the perifollicular zone. LZ- and DZ-FDCs form the FDC network in the B cell follicle. TBRCs line the interface of the B cell follicle and T cell zone. TRCs are localized to the T cell zone. (a) In lymph nodes, IFRCs support the areas between B cell follicles. PRCs and PI16-RCs or CD34⁺ stromal cells (CD34⁺ SC) support perivascular niches, and MedRCs locate to the medulla. (b) In the spleen, BCRCs support bridging channels. THY1⁺ TRCs, ARCs, and PRCs are located in the perivascular space around the central artery. (c) Subepithelial perivascular niches are supported by the TRC1 subset in murine Peyer’s patches and PI16-RCs in human palatine tonsils. PRCs support perivascular niches in T cell–rich tonsillar regions. M, microfold; FAE, follicle-associated epithelium; LEC, lymphatic endothelial cell.

Figure 2.

Molecular interactions between FRCs and leukocytes secure local niche specification and FRC function. (a–d) Representation of the key molecular signals exchanged between leukocytes and FRC subsets that furnish the antigen-sampling zone (a), B cell zone (b), T cell zone (c), and perivascular zones (d). (a) MRCs provided cues to secure niche developments and regulate survival and activation of CD169⁺ macrophages and B cells. (b) FDCs integrate and provide diverse cues for efficient antigen and Tfh cell encounter and topological GC rearrangement. (c) TRCs provide and receive signals for T cell and DC homeostasis and the regulation of T cell activation. (d) In perivascular regions, PRCs and PI16-RCs guide lymphocyte extravasation into SLOs and regulate T cell activity. Arrows indicate the directionality between receptor–ligand interactions. LEC, lymphatic endothelial cell; ECM, extracellular matrix.