Resident Memory T Cells in Synovial Tissue Mediate Arthritis Flares

Margaret Chang¹, Anais Levescot², Nathan Nelson-Maney², Rachel Blaustein², Kellen Winden¹, Allyn Morris³, Spoorthi Balu³, Alexandra Wactor², Ricardo Grieshaber-Bouyer⁴, Kevin Wei⁵, Lauren Henderson⁶, Rachael Clark³, Deepak Rao², Robert Fuhlbrigge⁷ and Peter Nigrovic⁸, ¹Boston Children's Hospital, Boston, MA, ²Brigham and Women's Hospital, Boston, MA, ³Brigham and Women's Hospital, Boston, ⁴Department of Medicine V, Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany; Division of Rheumatology, Inflammation and Immunity, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA, Heidelberg, Germany, ⁵Brigham and Women's Hospital and Harvard Medical School, Boston, MA, ⁶Boston Children's Hospital, Watertown, MA, ⁷University of Colorado, Denver, CO, ⁸Division of Rheumatology, Inflammation and Immunity, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA, Boston

Meeting: ACR Convergence 2020

Keywords: rheumatoid arthritis, Synovitis, T Cell

Session Information

Date: Monday, November 9, 2020

Title: T Cell Biology & Targets in Autoimmune & Inflammatory Disease (2043–2047)

Session Type: Abstract Session

Session Time: 10:00AM-10:50AM

Background/Purpose: Resident memory T cells (T_RM) are site-specific memory T cells that take up long-term residence in peripheral tissues and aid in local immune defense. T_RM have also been implicated in autoimmune diseases by driving localized recurrent inflammation. As chronic arthritis is characterized by recurrent site-specific joint inflammation, we sought to investigate the role of T_RMin joint-specific memory.

Methods: We performed 10x genomics droplet-based single cell RNA sequencing and immune repertoire profiling on memory T cells disaggregated from human rheumatoid arthritis synovium to evaluate transcriptomic signature. We also used Mantra multispectral immunofluorescence microscopy to evaluate T cells expressing common T_RM protein markers in human arthritic synovial tissue sections. To assess the functional contribution of T_RM cells in arthritis in vivo, we generated a novel murine model of joint-specific recurrent synovitis. We utilized adoptive transfer, in vitro metabolic and migration assays, in vivo cell labeling, and localized depletion strategies to characterize T_RM cells in the synovium and their functional role in arthritis flare.

Results: We identified cells with the phenotypic and transcriptomic signature of T_RM within human arthritic synovium. These cells were primarily CD8+ and exhibited restricted T cell receptor clonotypes as well as a pro-inflammatory gene expression profile. Adoptive transfer studies in our animal model of joint-specific recurrent inflammation confirmed that arthritis flares were mediated by antigen-specific CD8+ T cells that remained within previously inflamed joints during remission. These cells were bona fide T_RM, as confirmed through surface signature, failure to migrate in vivo or in vitro, preferential uptake of free fatty acids, and long-term residency. Site-specific depletion of synovial T cells during remission markedly ameliorated disease recurrence, establishing a role of synovial T_RM in arthritis flares.

Conclusion: Here, we demonstrate that synovial T_RM present in human inflamed synovium are a targetable mediator of joint-specific memory in arthritis.

Disclosure: M. Chang, None; A. Levescot, None; N. Nelson-Maney, None; R. Blaustein, None; K. Winden, None; A. Morris, None; S. Balu, None; A. Wactor, None; R. Grieshaber-Bouyer, None; K. Wei, Gilead, 5; L. Henderson, Adaptive Biotechnologies, 5, Sobi, 5, CARRA, 9; R. Clark, None; D. Rao, None; R. Fuhlbrigge, None; P. Nigrovic, Novartis, 2, 5, BMS, 2, 5, Pfizer, 2, 5, Sobi, 5, Miach Orthopedics, 5, Simcere, 5, XBiotech, 5, Quench Bio, 5, Siglion, 5, Cerecor, 5, UpToDate, 7, American Academy of Pediatrics, 7, CARRA, 9.

To cite this abstract in AMA style:

Chang M, Levescot A, Nelson-Maney N, Blaustein R, Winden K, Morris A, Balu S, Wactor A, Grieshaber-Bouyer R, Wei K, Henderson L, Clark R, Rao D, Fuhlbrigge R, Nigrovic P. Resident Memory T Cells in Synovial Tissue Mediate Arthritis Flares [abstract]. Arthritis Rheumatol. 2020; 72 (suppl 10). https://acrabstracts.org/abstract/resident-memory-t-cells-in-synovial-tissue-mediate-arthritis-flares/. Accessed .

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