Contributors: Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC); Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes (Biosit : Biologie - Santé - Innovation Technologique); Hospices Civils de Lyon (HCL); Université Claude Bernard Lyon 1 (UCBL); Université de Lyon; Biosit : biologie, santé, innovation technologique (SFR UMS CNRS 3480 - INSERM 018); Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes (Biosit : Biologie - Santé - Innovation Technologique); H2P2 - Histo Pathologie Hight Precision (H2P2); Université de Rennes (UR)-Structure Fédérative de Recherche en Biologie et Santé de Rennes (Biosit : Biologie - Santé - Innovation Technologique); Institut Curie Paris; CHU Montpellier; Centre Hospitalier Régional Universitaire Montpellier (CHRU Montpellier); Institut de Génétique Moléculaire de Montpellier (IGMM); Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS); Memorial Sloan Kettering Cancer Center (MSKCC); Centre Hospitalier Universitaire de Rennes CHU Rennes = Rennes University Hospital Pontchaillou; Etablissement français du sang Rennes (EFS Bretagne); This work is supported by the Fondation ARC pour la Recherche sur le Cancer (Grant PGA1 RF20170205386), the Institut National du cancer (INCA AAP PLBIO-17-06), the Agence Nationale de la Recherche (ANR, ANR-16-CE15-0019-03), and the LLS (TRP 6593-20). L.V. is recipient of a doctoral fellowship from the Labex IGO. S.L. is supported by a Chair d'Excellence of the Fondation Rennes 1 and Labex IGO. F.M. is supported by research grants from La Ligue Régionale contre le Cancer. Immunofluorescence studies were performed on the Microscopy Rennes Imaging Center (MRic) and on the H2P2 platform, both members of the UMS 6480 Biosit and of the national infrastructure France-BioImaging supported by the ANR (ANR-10-INBS-04). Cell sorting was performed at the UMS 6480 Biosit CytomeTRI facility. High-throughput sequencing has been performed by the ICGex NGS platform of the Institut Curie supported by the grants ANR-10-EQPX-03 (Equipex) and ANR-10-INBS-09-08 (France Génomique Consortium) from the ANR, by the ITMO-CANCER, and by the SiRIC-Curie program (SiRIC Grant INCa-DGOS-4654). The authors are indebted to the Centre de Ressources Biologiques (CRB)-Santé (BB-0033-00056) of Rennes hospital for the processing of biological samples, Christophe Ruaux for providing tonsil samples, Erwan Flecher for providing normal bone marrow samples, and the LYSA-P for generating TMA from patients included in the FLIRT trial (NCT02303119) sponsored by the Lymphoma Academic Research Organisation (LYSA).; ANR-16-CE15-0019,Ig-MemImpact,Rôle de la classe des Ig / BCR dans les interactions cellulaires supportant la mémoire immune et impact immunopathologique(2016); ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010); ANR-10-EQPX-0003,ICGex,Equipement de biologie intégrative du cancer pour une médecine personnalisée(2010); ANR-10-INBS-0009,France Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010)
نبذة مختصرة : International audience ; Lymphoid stromal cells (LSCs) are essential organizers of immune responses. We analyzed tonsillar tissue by combining flow cytometry, in situ imaging, RNA sequencing, and functional assays, defining three distinct human LSC subsets. The integrin CD49a designated perivascular stromal cells exhibiting features of local committed LSC precursors and segregated cytokine and chemokine-producing fibroblastic reticular cells (FRCs) supporting B and T cell survival. The follicular dendritic cell transcriptional profile reflected active responses to B cell and non-B cell stimuli. We therefore examined the effect of B cell stimuli on LSCs in follicular lymphoma (FL). FL B cells interacted primarily with CD49a(+) FRCs. Transcriptional analyses revealed LSC reprogramming in situ downstream of the cytokines tumor necrosis factor (TNF) and transforming growth factor β (TGF-β), including increased expression of the chemokines CCL19 and CCL21. Our findings define human LSC populations in healthy tissue and reveal bidirectional crosstalk between LSCs and malignant B cells that may present a targetable axis in lymphoma.
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