Contributors: Microenvironment and B-cells: Immunopathology,Cell Differentiation, and Cancer (MOBIDIC); Université de Rennes (UR)-Etablissement français du sang Rennes (EFS Bretagne)-Institut National de la Santé et de la Recherche Médicale (INSERM); Etablissement Français du Sang Bretagne; EFS; Centre Hospitalier Universitaire Rennes; 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); University of Barcelona; This work was supported by research grants from the Institut National duCancer (PLBIO-18-060), the Ligue Nationale Contre le Cancer(Equipe Labellisée) and the Carnot-CALYM institute. SR has been funded by a researcher grant from the Brittany Region (SAD #9278).; This work was realized in the context of the LabEX IGO program (n° ANR-11-LABX-0016) funded by the «Investment into the Future» French Government program, managed by the National Research Agency (ANR). The authors are thankful to the Centre de Ressources Biologiques (CRB)-Sant́e (BB-0033-00056, http://www.crbsante-rennes.com) of Rennes Hospital for its support in the processing of biological samples, the Clinique La Sagesse and Christophe Ruaux for providing the tonsil samples, and the UMS CNRS 3480/US INSERM 018 BIOSIT for the cell sorting core facility. The authors thank Violaine Alunni from the IGBMC Microarray and Sequencing platform (Illkrich Graffestaden, France) for Affymetrix GeneChip analysis. The authors thank Birgitt Sawitzki (Charity Hospital, Berlin, Germany) for TSDR methylation assessments.; ANR-11-LABX-0016,IGO,Immunothérapies Grand Ouest(2011)
نبذة مختصرة : International audience ; Introduction: Follicular Lymphoma (FL) results from the malignant transformation of germinal center (GC) B cells. FL B cells display recurrent and diverse genetic alterations, some of them favoring their direct interaction with their cell microenvironment, including follicular helper T cells (Tfh). Although FL-Tfh key role is well-documented, the impact of their regulatory counterpart, the follicular regulatory T cell (Tfr) compartment, is still sparse.Methods: The aim of this study was to characterize FL-Tfr phenotype by cytometry, gene expression profile, FL-Tfr origin by transcriptomic analysis, and functionality by in vitro assays.Results: CD4+CXCR5+CD25hiICOS+ FL-Tfr displayed a regulatory program that is close to classical regulatory T cell (Treg) program, at the transcriptomic and methylome levels. Accordingly, Tfr imprinting stigmata were found on FL-Tfh and FL-B cells, compared to their physiological counterparts. In addition, FL-Tfr co-culture with autologous FL-Tfh or cytotoxic FL-CD8+ T cells inhibited their proliferation in vitro. Finally, although FL-Tfr shared many characteristics with Treg, TCR sequencing analyses demonstrated that part of them derived from precursors shared with FL-Tfh.Discussion: Altogether, these findings uncover the role and origin of a Tfr subset in FL niche and may be useful for lymphomagenesis knowledge and therapeutic management.
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