Antigen-driven PD-1+ TOX+ BHLHE40+ and PD-1+ TOX+ EOMES+ T lymphocytes regulate juvenile idiopathic arthritis in situ

Patrick Maschmeyer; Gitta Anne Heinz; Christopher Mark Skopnik; Lisanne Lutter; Alessio Mazzoni; Frederik Heinrich; Sae Lim von Stuckrad; Lorenz Elias Wirth; Cam Loan Tran; René Riedel; Katrin Lehmann; Imme Sakwa; Rolando Cimaz; Francesco Giudici; Marcus Alexander Mall; Philipp Enghard; Bas Vastert; Hyun-Dong Chang; Pawel Durek; Francesco Annunziato; Femke van Wijk; Andreas Radbruch; Tilmann Kallinich; Mir-Farzin Mashreghi

doi:10.1002/eji.202048797

Antigen-driven PD-1⁺ TOX⁺ BHLHE40⁺ and PD-1⁺ TOX⁺ EOMES⁺ T lymphocytes regulate juvenile idiopathic arthritis in situ

Eur J Immunol. 2021 Apr;51(4):915-929. doi: 10.1002/eji.202048797. Epub 2021 Feb 2.

Authors

Patrick Maschmeyer¹, Gitta Anne Heinz¹, Christopher Mark Skopnik², Lisanne Lutter³, Alessio Mazzoni⁴, Frederik Heinrich¹, Sae Lim von Stuckrad^{5

6}, Lorenz Elias Wirth¹, Cam Loan Tran¹, René Riedel¹, Katrin Lehmann¹, Imme Sakwa¹, Rolando Cimaz^{7

8}, Francesco Giudici⁹, Marcus Alexander Mall^{5

10}, Philipp Enghard², Bas Vastert³, Hyun-Dong Chang¹, Pawel Durek^{1

11}, Francesco Annunziato⁴, Femke van Wijk³, Andreas Radbruch¹, Tilmann Kallinich^{1

5

10}, Mir-Farzin Mashreghi^{1

11}

Affiliations

¹ Deutsches Rheuma-Forschungszentrum (DRFZ), Institute of the Leibniz Association, Berlin, Germany.
² Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Nephrology and Intensive Care Medicine, Berlin, Germany.
³ Center for Translational Immunology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.
⁴ Department of Experimental and Clinical Medicine and DENOTHE Center, University of Florence, Florence, Italy.
⁵ Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Pediatric Pulmonology, Immunology and Critical Care Medicine, Berlin, Germany.
⁶ Charité - Universitätsmedizin Berlin, corporate member of Freie Universität, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin SPZ (Center for Chronically Sick Children), Berlin, Germany.
⁷ Anna Meyer Children's Hospital and University of Florence, Florence, Italy.
⁸ Department of Clinical Sciences and Community Health, University of Milano, Milano, Italy.
⁹ Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
¹⁰ Berlin Institute of Health (BIH), Berlin, Germany.
¹¹ BCRT/DRFZ Single-Cell Laboratory for Advanced Cellular Therapies - Brandenburg Center for Regenerative Therapies (BCRT), Berlin, Germany.

PMID: 33296081
DOI: 10.1002/eji.202048797

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.

Keywords: BHLHE40; EOMES; PD-1; T cells; TOX; chronic inflammation; juvenile idiopathic arthritis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antigens / immunology*
Arthritis, Juvenile / genetics
Arthritis, Juvenile / immunology*
Arthritis, Juvenile / metabolism
Basic Helix-Loop-Helix Transcription Factors / immunology*
Basic Helix-Loop-Helix Transcription Factors / metabolism
CD4-Positive T-Lymphocytes / immunology
CD4-Positive T-Lymphocytes / metabolism
CD8-Positive T-Lymphocytes / immunology
CD8-Positive T-Lymphocytes / metabolism
Cells, Cultured
Gene Expression Profiling / methods
High Mobility Group Proteins / immunology*
High Mobility Group Proteins / metabolism
Homeodomain Proteins / immunology*
Homeodomain Proteins / metabolism
Humans
Programmed Cell Death 1 Receptor / immunology*
Programmed Cell Death 1 Receptor / metabolism
RNA-Seq / methods
Receptors, Antigen, T-Cell / genetics
Receptors, Antigen, T-Cell / immunology
Receptors, Antigen, T-Cell / metabolism
Single-Cell Analysis / methods
T-Box Domain Proteins / immunology*
T-Box Domain Proteins / metabolism
T-Lymphocytes / immunology*
T-Lymphocytes / metabolism
Transcriptome / genetics
Transcriptome / immunology

Substances

Antigens
BHLHE40 protein, human
Basic Helix-Loop-Helix Transcription Factors
EOMES protein, human
High Mobility Group Proteins
Homeodomain Proteins
Programmed Cell Death 1 Receptor
Receptors, Antigen, T-Cell
T-Box Domain Proteins
TOX protein, human