TY - JOUR
T1 - Antigen-driven PD-1+ TOX+ BHLHE40+ and PD-1+ TOX+ EOMES+ T lymphocytes regulate juvenile idiopathic arthritis in situ
AU - Maschmeyer, Patrick
AU - Heinz, Gitta Anne
AU - Skopnik, Christopher Mark
AU - Lutter, Lisanne
AU - Mazzoni, Alessio
AU - Heinrich, Frederik
AU - von Stuckrad, Sae Lim
AU - Wirth, Lorenz Elias
AU - Tran, Cam Loan
AU - Riedel, René
AU - Lehmann, Katrin
AU - Sakwa, Imme
AU - Cimaz, Rolando
AU - Giudici, Francesco
AU - Mall, Marcus Alexander
AU - Enghard, Philipp
AU - Vastert, Bas
AU - Chang, Hyun-Dong
AU - Durek, Pawel
AU - Annunziato, Francesco
AU - van Wijk, Femke
AU - Radbruch, Andreas
AU - Kallinich, Tilmann
AU - Mashreghi, Mir-Farzin
N1 - 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
PY - 2021/4
Y1 - 2021/4
N2 - 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 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.
AB - 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 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.
KW - BHLHE40
KW - chronic inflammation
KW - EOMES
KW - juvenile idiopathic arthritis
KW - PD-1
KW - T cells
KW - TOX
UR - https://www.scopus.com/pages/publications/85100086972
U2 - 10.1002/eji.202048797
DO - 10.1002/eji.202048797
M3 - Article
C2 - 33296081
SN - 0014-2980
VL - 51
SP - 915
EP - 929
JO - European Journal of Immunology
JF - European Journal of Immunology
IS - 4
ER -