Modeling resident memory T cell development in arthritis with human 3D synovial organoids reveals inflammation-triggered T cell-stromal cell interactions
Presentation Time: 03:15 PM - 04:30 PM
Poster Board Number: B528
Abstract ID: 5076
Presenting Author:
Margaret H Chang , Assistant Professor at Boston Children's Hosp., Harvard Med. Sch.
Abstract:
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint-specific memory. We identified CD8+ resident memory T cells (TRM) in human arthritic joints and demonstrated that TRM remain in the synovium during remission and mediate arthritis flares in murine models. Strategies to model synovial TRM in human arthritis are lacking. To recapitulate the synovial structure in 3D organoids, we encapsulated fibroblast-like synoviocytes (FLS) from human RA donors with endothelial cells (HUVEC) in Matrigel. CD8+ memory T cells from the blood of healthy donors were co-cultured with the synovial organoid for 3 weeks. TRM development was validated by cell surface phenotype, gene expression profile, enhanced free fatty acid uptake and lack of migratory response to tissue egress signals. To simulate inflammation, synovial stromal cells were challenged with inflammatory cytokines and production of IL-15 or TGFbeta, known mediators of TRM development, was assessed. TNF stimulated an increase in IL-15 expression by FLS but not HUVEC, while TGFbeta was unchanged. Upregulation of IL-15 was specific to TNF and not a general response to inflammatory cytokines. Exposure to TNF enhanced TRM development in the synovial organoid, while inhibition with IL-15 or CD122 blocking antibodies reduced TRM formation. As synovial TRM mediate arthritis chronicity and flares, developing effective methods to target synovial TRM represent a critical pathway towards durable disease control.
Modeling resident memory T cell development in arthritis with human 3D synovial organoids reveals inflammation-triggered T cell-stromal cell interactions
Category
Poster and Podium (Block Symposium)