Synovial tissue myeloid dendritic cell subsets exhibit distinct tissue-niche localization and function in health and rheumatoid arthritis

Lucy MacDonald; Aziza Elmesmari; Domenico Somma; Jack Frew; Clara Di Mario; Roopa Madhu; Audrey Paoletti; Theodoros Simakou; Olympia M Hardy; Barbara Tolusso; Denise Campobasso; Simone Perniola; Marco Gessi; Maria Rita Gigante; Luca Petricca; Dario Bruno; Lavinia Agra Coletto; Roberta Benvenuto; John D Isaacs; Andrew Filby; David McDonald; Jasmine P X Sim; Nigel Jamieson; Kevin Wei; Maria Antonietta D'Agostino; Neal L Millar; Simon Milling; Charles McSharry; Elisa Gremese; Karen Affleck; Kenneth F Baker; Iain B McInnes; Thomas D Otto; Ilya Korsunsky; Stefano Alivernini; Mariola Kurowska-Stolarska

doi:10.1016/j.immuni.2024.11.004

Synovial tissue myeloid dendritic cell subsets exhibit distinct tissue-niche localization and function in health and rheumatoid arthritis

Immunity. 2024 Dec 10;57(12):2843-2862.e12. doi: 10.1016/j.immuni.2024.11.004. Epub 2024 Nov 27.

Authors

Lucy MacDonald¹, Aziza Elmesmari¹, Domenico Somma¹, Jack Frew¹, Clara Di Mario², Roopa Madhu³, Audrey Paoletti⁴, Theodoros Simakou¹, Olympia M Hardy¹, Barbara Tolusso², Denise Campobasso², Simone Perniola⁵, Marco Gessi⁶, Maria Rita Gigante⁷, Luca Petricca⁷, Dario Bruno⁸, Lavinia Agra Coletto⁹, Roberta Benvenuto⁶, John D Isaacs¹⁰, Andrew Filby¹¹, David McDonald¹¹, Jasmine P X Sim¹², Nigel Jamieson¹³, Kevin Wei¹⁴, Maria Antonietta D'Agostino⁷, Neal L Millar¹, Simon Milling¹, Charles McSharry¹⁵, Elisa Gremese⁸, Karen Affleck¹⁶, Kenneth F Baker¹⁰, Iain B McInnes¹, Thomas D Otto¹, Ilya Korsunsky³, Stefano Alivernini¹⁷, Mariola Kurowska-Stolarska¹⁸

Affiliations

¹ Research into Inflammatory Arthritis Centre Versus Arthritis (RACE), Glasgow, UK; School of Infection & Immunity, University of Glasgow, Glasgow, UK.
² Immunology Research Core Facility, Gemelli Science and Technology Park, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.
³ Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02141, USA.
⁴ School of Infection & Immunity, University of Glasgow, Glasgow, UK.
⁵ Immunology Research Core Facility, Gemelli Science and Technology Park, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; Division of Clinical Immunology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.
⁶ Institute of Pathology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.
⁷ Division of Rheumatology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.
⁸ Research into Inflammatory Arthritis Centre Versus Arthritis (RACE), Glasgow, UK; Immunology Research Core Facility, Gemelli Science and Technology Park, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; Division of Clinical Immunology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.
⁹ Research into Inflammatory Arthritis Centre Versus Arthritis (RACE), Glasgow, UK; School of Infection & Immunity, University of Glasgow, Glasgow, UK; Immunology Research Core Facility, Gemelli Science and Technology Park, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.
¹⁰ Research into Inflammatory Arthritis Centre Versus Arthritis (RACE), Glasgow, UK; Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK; Musculoskeletal Unit, Newcastle-upon-Tyne Hospitals, Newcastle upon Tyne, UK.
¹¹ Flow Cytometry Core Facility, Newcastle University, Newcastle upon Tyne, UK.
¹² Research into Inflammatory Arthritis Centre Versus Arthritis (RACE), Glasgow, UK; Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
¹³ School of Cancer Sciences, University of Glasgow, Glasgow, UK.
¹⁴ Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
¹⁵ School of Infection & Immunity, University of Glasgow, Glasgow, UK; NHS Greater Glasgow and Clyde, Glasgow, UK.
¹⁶ Respiratory and Immunology Research Unit, GSK, Stevenage, UK.
¹⁷ Research into Inflammatory Arthritis Centre Versus Arthritis (RACE), Glasgow, UK; School of Infection & Immunity, University of Glasgow, Glasgow, UK; Immunology Research Core Facility, Gemelli Science and Technology Park, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; Division of Rheumatology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy. Electronic address: [email protected].
¹⁸ Research into Inflammatory Arthritis Centre Versus Arthritis (RACE), Glasgow, UK; School of Infection & Immunity, University of Glasgow, Glasgow, UK. Electronic address: [email protected].

PMID: 39609125
DOI: 10.1016/j.immuni.2024.11.004

Abstract

Current rheumatoid arthritis (RA) treatments do not restore immune tolerance. Investigating dendritic cell (DC) populations in human synovial tissue (ST) may reveal pathways to reinstate tolerance in RA. Using single-cell and spatial transcriptomics of ST biopsies, as well as co-culture systems, we identified condition- and niche-specific DC clusters with distinct functions. Healthy tissue contained tolerogenic AXL⁺ DC2s in the lining niche. In active RA, the hyperplasic lining niche was populated with inflammatory DC3s that activated CCL5-positive effector memory T cells, promoting synovitis. Lymphoid niches that emerged in the sublining layer were enriched with CCR7⁺ DC2s, which interacted with naive T cells, potentially driving the local expansion of new effector T cells. Remission saw the resolution of these pathogenic niches but lacked recovery of tolerogenic DC2s and exhibited activation of blood precursors of ST-DC3 clusters prior to flare-ups. Targeting pathogenic DC3s or restoring tolerogenic DC2s may help restore immune homeostasis in RA joints.

Keywords: T cells; arthritis; dendritic cells; disease remission; immune tolerance; spatial transcriptomics; synovial tissue.

MeSH terms

Arthritis, Rheumatoid* / immunology
Coculture Techniques
Dendritic Cells* / immunology
Female
Humans
Immune Tolerance
Male
Memory T Cells / immunology
Memory T Cells / metabolism
Middle Aged
Myeloid Cells / immunology
Myeloid Cells / metabolism
Single-Cell Analysis
Synovial Membrane* / immunology