Article
NK cell-derived interferon-γ induces pro-inflammatory MHC-II+ synovial fibroblasts in rheumatoid arthritis
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Authors
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Wolfgang Merkt
- Medizinische Klinik V, University Clinic Heidelberg, Heidelberg; Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston
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Shuyang Zhao
- Medizinische Klinik V, University Clinic Heidelberg, Heidelberg
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Deepak Rao
- Human Immunology Center, Brigham and Women’s Hospital, Harvard Medical School, Boston
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Hanns-Martin Lorenz
- Medizinische Klinik V, University Clinic Heidelberg, Heidelberg
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Lars-Oliver Tykocinski
- Medizinische Klinik V, University Clinic Heidelberg, Heidelberg
| Published: | September 9, 2020 |
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Outline
Text
Introduction: A recent resource study identified fibroblast subsets in rheumatoid arthritis (RA) [1]. One of these subsets is characterized by a high, atypical MHC-II expression, a pro-inflammatory phenotype and signatures of genes involved in interferon-γ signaling and antigen presentation. MHC-II+ synovial fibroblasts can indeed engulf, digest and present antigens to CD4+ T cells [2]. In the present study, we investigated mechanisms underlying the development of this pro-inflammatory synovial fibroblast subset.
Methods: Primary synovial fibroblasts were isolated from synovial tissues collected during joint replacement surgeries. Natural Killer (NK) cells and CD4+ T cells were isolated from healthy volunteers. Mass cytometry data from synovial biopsies were generated under the umbrella of the Accelerated Medicine Partnership (AMP-RA/SLE) Consortium.
Results: Using an in vitro co-culture system, we showed that interferon-γ released from activated NK cells induced MHC-II expression on synovial fibroblasts from osteoarthritis (OA) and RA patients. The crosslinking of MHC-II on synovial fibroblasts to T cell receptors with a superantigen induced a robust activation of CD4+ T cells. However, synovial fibroblasts that were pre-treated with NK cell-derived interferon-γ also activated CD4+ T cells without crosslinking MHC-II and T cell receptors. This MHC-II-independent effect was 4x stronger when culturing T cells on RA compared to OA fibroblasts. Wondering whether synovial fibroblasts may be in contact with NK cells in vivo, we analyzed mass cytometry data generated from synovial biopsies. NK cells were detectable, and possessed a more activated phenotype in RA compared to OA. Upadacitinib, a selective JAK1 inhibitor, blocked the effect of NK cell-derived interferon-γ on synovial fibroblasts and prevented MHC-II induction and pro-inflammatory signals to T cells.
Conclusion: Together, we suggest activated synovial NK cells as a source of interferon-γ which in turn induces the newly described pro-inflammatory MHC-II+ synovial fibroblast subset in RA. JAK inhibition with Upadacitinib is effective in suppressing this novel pathway in inflammatory arthritis.
Disclosures: None declared
References
- 1.
- Zhang F, Wei K, Slowikowski K, Fonseka CY, Rao DA, Kelly S, Goodman SM, Tabechian D, Hughes LB, Salomon-Escoto K, et al. Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry. Nat Immunol. 2019;20(7):928-42.
- 2.
- Carmona-Rivera C, Carlucci PM, Moore E, Lingampalli N, Uchtenhagen H, James E, Liu Y, Bicker KL, Wahamaa H, Hoffmann V, et al. Synovial fibroblast-neutrophil interactions promote pathogenic adaptive immunity in rheumatoid arthritis. Sci Immunol. 2017 Apr;2(10):eaag3358. DOI: 10.1126/sciimmunol.aag3358
