Lymph node fibroblast phenotypes and immune crosstalk regulated by podoplanin activity
Spyridon Makris,
Yukti Hari-Gupta,
Jesús A. Cantoral-Rebordinos,
Victor G. Martinez,
Harry L. Horsnell,
Agnesska C. Benjamin,
Isabella Cinti,
Martina Jovancheva,
Daniel Shewring,
Nicola Nguyen,
Charlotte M. de Winde,
Alice E. Denton,
Sophie E. Acton
Affiliations
Spyridon Makris
Stromal Immunology Group, MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT, UK
Yukti Hari-Gupta
Stromal Immunology Group, MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT, UK
Jesús A. Cantoral-Rebordinos
Stromal Immunology Group, MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT, UK; Stem Cell and Human Development Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
Victor G. Martinez
Stromal Immunology Group, MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT, UK; Molecular Oncology Unit, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), Madrid, Spain
Harry L. Horsnell
Stromal Immunology Group, MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT, UK
Agnesska C. Benjamin
Stromal Immunology Group, MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT, UK
Isabella Cinti
Department of Immunology and Inflammation, Imperial College London, London W12 0NN, UK
Martina Jovancheva
Stromal Immunology Group, MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT, UK
Daniel Shewring
Stromal Immunology Group, MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT, UK
Nicola Nguyen
Stromal Immunology Group, MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT, UK
Charlotte M. de Winde
Stromal Immunology Group, MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT, UK; Department for Molecular Cell Biology and Immunology, Amsterdam UMC, Location VUmc, De Boelelaan 1108, 1081 HZ Amsterdam, the Netherlands
Alice E. Denton
Department of Immunology and Inflammation, Imperial College London, London W12 0NN, UK
Sophie E. Acton
Stromal Immunology Group, MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT, UK; Corresponding author
Summary: Lymph nodes are uniquely organized niches for immune interactions. Fibroblastic reticular cells (FRCs) facilitate immune cell communication and regulate immune function by producing growth factors, chemokines, and inflammatory cues. Stromal expression of the glycoprotein podoplanin (PDPN) is required for lymph node development, but the requirement for PDPN signaling in FRCs in adult lymph nodes has not been directly tested. Using a conditional in vivo deletion model PDGFRαmGFPΔPDPN, single-cell RNA sequencing (scRNA-seq) reveals that PDPN deletion increases inflammatory signaling in lymph nodes and disrupts stromal-immune cell crosstalk in steady state and during adaptive immune responses. We confirm that PDPN/CLEC-2 signaling in FRCs switches transcriptional states and alters the expression of immune-related genes. We conclude that PDPN expression impacts the immunoregulatory properties of fibroblastic stroma in lymph nodes and is a key transcriptional regulator of fibroblast function in lymph nodes.
