Antigen-driven PD-1+ TOX+ BHLHE40+ and PD-1+ TOX+ EOMES+ T lymphocytes regulate juvenile idiopathic arthritis in situ
Maschmeyer, Patrick; Heinz, Gitta Anne; Skopnik, Christopher Mark; Lutter, Lisanne; Mazzoni, Alessio; Heinrich, Frederik; von Stuckrad, Sae Lim; Wirth, Lorenz Elias; Tran, Cam Loan; Riedel, René; Lehmann, Katrin; Sakwa, Imme; Cimaz, Rolando; Giudici, Francesco; Mall, Marcus Alexander; Enghard, Philipp; Vastert, Bas; Chang, Hyun-Dong; Durek, Pawel; Annunziato, Francesco; van Wijk, Femke; Radbruch, Andreas; Kallinich, Tilmann; Mashreghi, Mir-Farzin
(2021) European Journal of Immunology, volume 51, issue 4, pp. 915 - 929
(Article)
Abstract
T lymphocytes accumulate in inflamed tissues of patients with chronic inflammatory diseases (CIDs) and express pro-inflammatory cytokines upon re-stimulation in vitro. Further, a significant genetic linkage to MHC genes suggests that T lymphocytes play an important role in the pathogenesis of CIDs including juvenile idiopathic arthritis (JIA). However, the functions
... read more
of T lymphocytes in established disease remain elusive. Here we dissect the transcriptional and the clonal heterogeneity of synovial T lymphocytes in JIA patients by single-cell RNA sequencing combined with T cell receptor profiling on the same cells. We identify clonally expanded subpopulations of T lymphocytes expressing genes reflecting recent activation by antigen in situ. A PD-1+ TOX+ EOMES+ population of CD4+ T lymphocytes expressed immune regulatory genes and chemoattractant genes for myeloid cells. A PD-1+ TOX+ BHLHE40+ population of CD4+ , and a mirror population of CD8+ T lymphocytes expressed genes driving inflammation, and genes supporting B lymphocyte activation in situ. This analysis points out that multiple types of T lymphocytes have to be targeted for therapeutic regeneration of tolerance in arthritis.
show less
Download/Full Text
Keywords: BHLHE40, chronic inflammation, EOMES, juvenile idiopathic arthritis, PD-1, T cells, TOX, Immunology and Allergy, Immunology, Journal Article
ISSN: 0014-2980
Publisher: Wiley-VCH Verlag
Note: Funding Information: This work was supported by the state of Berlin and the “European Regional Development Fund” (ERDF 2014–2020, EFRE 1.8/11, Deutsches Rheuma‐Forschungszentrum to M.F.M.), Deutsche Forschungsgemeinschaft through DFG priority program 1468 IMMUNOBONE and the TRR130 (to A.R. and H.D.C.) and by the European Research Council through the Advanced Grant IMMEMO (ERC‐2010‐AdG.20100317 Grant 268978 to AR), the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 777357, the Rheumastiftung (to H.D.C.) and the Leibniz Science Campus Chronic Inflammation ( www.chronische-entzuendung.org ). P.M. has been supported by EUTRAIN, a FP7 Marie Curie Initial Training Network for Early Stage Researchers funded by the European Union (FP7‐PEOPLE‐2011‐ITN‐289903). H.D.C. is funded by the Dr. Rolf M. Schwiete Foundation. M.A.M. has been supported by the Einstein Foundation Berlin (EP‐2017‐393). C.M.S. is supported by the Deutsche Forschungsgemeinschaft (DFG; EN 924/5‐1). F.W. and L.L. were supported by a VIDI grant from ZonMw (91714332). We thank Fahd Qadir (GitHub user Dragonmasterx87) for providing code to transfer data from Seurat to Monocle. Funding Information: This work was supported by the state of Berlin and the ?European Regional Development Fund? (ERDF 2014?2020, EFRE 1.8/11, Deutsches Rheuma-Forschungszentrum to M.F.M.), Deutsche Forschungsgemeinschaft through DFG priority program 1468 IMMUNOBONE and the TRR130 (to A.R. and H.D.C.) and by the European Research Council through the Advanced Grant IMMEMO (ERC-2010-AdG.20100317 Grant 268978 to AR), the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 777357, the Rheumastiftung (to H.D.C.) and the Leibniz Science Campus Chronic Inflammation (www.chronische-entzuendung.org). P.M. has been supported by EUTRAIN, a FP7 Marie Curie Initial Training Network for Early Stage Researchers funded by the European Union (FP7-PEOPLE-2011-ITN-289903). H.D.C. is funded by the Dr. Rolf M. Schwiete Foundation. M.A.M. has been supported by the Einstein Foundation Berlin (EP-2017-393). C.M.S. is supported by the Deutsche Forschungsgemeinschaft (DFG; EN 924/5-1). F.W. and L.L. were supported by a VIDI grant from ZonMw (91714332). We thank Fahd Qadir (GitHub user Dragonmasterx87) for providing code to transfer data from Seurat to Monocle. Open access funding enabled and organized by Projekt DEAL. Publisher Copyright: © 2021 The Authors. European Journal of Immunology published by Wiley-VCH GmbH
(Peer reviewed)
