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  • Review Article
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Lymph node fibroblastic reticular cells in health and disease

Nature Reviews Immunology volume 15, pages 350–361 (2015)Cite this article

Subjects

Key Points

  • Fibroblastic reticular cells (FRCs) are heterogeneous stromal cells. Subsets of FRCs include: T cell zone reticular cells that produce interleukin-7 (IL-7) to support naive T cells; resident and inducible B cell zone reticular cells that support naive B cells and follicle integrity; pericytic FRCs that support high endothelial venule (HEV) barrier function; follicular dendritic cells (FDCs) that support germinal centre function; and marginal reticular cells that can differentiate into FDCs.

  • Crucial checkpoints in mesenchymal stromal cell development are retinoic acid signalling to mesenchymal progenitor cells, which creates the lymph node anlage, followed by the attraction of lymphotoxin ligand-bearing group 3 innate lymphoid cells (usually mediated by CXC-chemokine ligand 13 (CXCL13)). Lymphotoxin-β receptor (LTβR) signalling to mesenchymal precursor cells results in the development of CC-chemokine ligand 19 (CCL19)+CCL21+CXCL13+ receptor activator of NF-κB ligand (RANKL)+LTβR+ mucosal vascular addressin cell adhesion molecule 1 (MADCAM1)+ lymphoid tissue organizer cells (LTo cells). Although it is still unclear precisely how LTo cells relate to mature FRCs, an immature FRC subset has been identified that requires LTβR signalling for the acquisition of an immunologically mature phenotype.

  • FRCs give lymph nodes the flexibility to stretch and to contract to accommodate the trapping of naive lymphocytes during an active immune response. Podoplanin (PDPN) maintains tension in the FRC network during homeostatic conditions, and this function is inhibited during an immune response when an influx of dendritic cells expressing C-type lectin domain family 1 member B (commonly known as CLEC2) inhibits PDPN-mediated FRC contractility.

  • During a chronic infection such as with HIV-1, regulatory T cells upregulate transforming growth factor-β1 (TGFβ1) production, which signals to FRCs to markedly increase their extracellular matrix production. Naive T cells can no longer physically contact FRCs and lose access to IL-7, which results in widespread T cell death and prolonged immunodeficiency.

  • Therapeutic advances seeking to mimic or target FRC function include antifibrotic drugs to reverse lymph node fibrosis, the administration of recombinant IL-7 to support T cell recovery after immunodepletion, and the use of FRCs as a putative anti-inflammatory cell therapy.

Abstract

Over the past decade, a series of discoveries relating to fibroblastic reticular cells (FRCs) — immunologically specialized myofibroblasts found in lymphoid tissue — has promoted these cells from benign bystanders to major players in the immune response. In this Review, we focus on recent advances regarding the immunobiology of lymph node-derived FRCs, presenting an updated view of crucial checkpoints during their development and their dynamic control of lymph node expansion and contraction during infection. We highlight the robust effects of FRCs on systemic B cell and T cell responses, and we present an emerging view of FRCs as drivers of pathology following acute and chronic viral infections. Lastly, we review emerging therapeutic advances that harness the immunoregulatory properties of FRCs.

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Figure 1: Molecular checkpoints in FRC development.
Figure 2: FRCs organize the lymph node microarchitecture.
Figure 3: Dynamic response of FRCs to infection.
Figure 4: Viral pathology drives FRC-mediated immunodeficiency.

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Acknowledgements

This work was supported by a Birmingham Fellowship (to A.L.F.) and a Henry Wellcome Fellowship (to S.E.A.). The authors thank J. Caamano for thoughtful suggestions on the manuscript and apologise to others whose work was not cited in this Review owing to space limitations.

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Authors and Affiliations

  1. School of Immunity and Infection, Institute of Biomedical Research, University of Birmingham, Edgbaston, B15 2TT, West Midlands, UK

    Anne L. Fletcher & Konstantin Knoblich

  2. Immunobiology Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, WC2A 3LY, London, UK

    Sophie E. Acton

  3. Department of Cell and Developmental Biology, University College London, Gower Street, WC1E 6BT, London, UK

    Sophie E. Acton

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Correspondence to Anne L. Fletcher.

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A.L.F. is an inventor on a patent related to the therapeutic use of fibroblastic reticular cells. S.E.A. and K.K. declare no competing interests.

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PowerPoint slides

Glossary

Myofibroblasts

Cells that share characteristics with fibroblasts and smooth muscle cells and that are often associated with the response to inflammation.

Follicular dendritic cells

(FDCs). Non-haematopoietic stromal cells found in B cell follicles that have an important role in antigen presentation to B cells.

Lymphoid tissue organizer cells

(LTo cells). CXC-chemokine ligand 13 (CXCL13)+ lymphotoxin-β receptor (LTβR)+ podoplanin (PDPN)+CD45− mesenchymal stromal cells that engage in molecular crosstalk with lymphoid tissue inducer cells to induce lymph node formation.

Lymphoid tissue inducer cells

(LTi cells; a subset of group 3 innate lymphoid cells). CD3−CD4+CD45+ innate lymphocytes that engage in crucial, carefully regulated molecular crosstalk with non-haematopoietic lymphoid tissue organizer cells to induce lymph node formation. Their development is dependent on the transcription factor retinoic acid receptor-related orphan receptor-γt (RORγt).

Autoimmune regulator

(AIRE). A transcriptional modulator primarily expressed by thymic medullary epithelial cells, in which it enhances the transcription of tissue-restricted antigens. This facilitates T cell education, by enabling developing T cells to encounter a large range of self proteins.

Ezrin, radixin and moesin family proteins

(ERM family proteins). Proteins that link the plasma membrane to the actin cytoskeleton. They are involved in cell adhesion, contraction and cortical morphogenesis.

Ccl19–Cre × Ltbrfl/fl mice

A BAC transgenic mouse model using CC-chemokine ligand 19 (Ccl19) promoter activity to target Cre recombinase to fibroblastic reticular cells and related cells. When crossed to the Ltbrfl/fl mouse, Cre recombinase deletes the lymphotoxin-β receptor (Ltbr) gene in any CCL19+ cells at the moment that CCL19 becomes upregulated.

Ccl19–Cre × iDTR mice

A BAC transgenic mouse model using CC-chemokine ligand 19 (Ccl19) promoter activity to target Cre recombinase to fibroblastic reticular cells (FRCs) and related cells. When crossed to the Cre-inducible diphtheria toxin receptor (iDTR) mouse, administration of diphtheria toxin depletes CCL19+ cells, including FRCs.

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Fletcher, A., Acton, S. & Knoblich, K. Lymph node fibroblastic reticular cells in health and disease. Nat Rev Immunol 15, 350–361 (2015). https://doi.org/10.1038/nri3846

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