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.
Antigen-driven PD-1+TOX+BHLHE40+ and PD-1+TOX+EOMES+ T lymphocytes regulate juvenile idiopathic arthritis in situ / Maschmeyer P.; Heinz G.A.; Skopnik C.M.; Lutter L.; Mazzoni A.; Heinrich F.; von Stuckrad S.L.; Wirth L.E.; Tran C.L.; Riedel R.; Lehmann K.; Sakwa I.; Cimaz R.; Giudici F.; Mall M.A.; Enghard P.; Vastert B.; Chang H.-D.; Durek P.; Annunziato F.; van Wijk F.; Radbruch A.; Kallinich T.; Mashreghi M.-F.. - In: EUROPEAN JOURNAL OF IMMUNOLOGY. - ISSN 0014-2980. - ELETTRONICO. - 51:(2021), pp. 915-929. [10.1002/eji.202048797]
Antigen-driven PD-1+TOX+BHLHE40+ and PD-1+TOX+EOMES+ T lymphocytes regulate juvenile idiopathic arthritis in situ
Mazzoni A.;Cimaz R.;Giudici F.;Annunziato F.;
2021
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 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.
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