Background/Purpose: Resident memory T cells (TRM) are site-specific memory T cells that take up long-term residence in peripheral tissues and aid in pathogen defense. However, TRM cells can also drive localized, recurrent inflammation. RA and JIA are characterized by recurrent joint inflammation that exhibits a strong tendency to flare at the same sites. We previously created a novel murine model of recurrent, joint-specific inflammation and demonstrated a population of memory T cells with a TRM cell phenotype (CD45+CD3+CD8+CD44+CD62L-CD69hi). Here, we characterize the persistence of these synovial resident memory T cells and their role in arthritis flares.

Methods: Localized arthritis is established by intra-articular (IA) injection of methylated bovine serum albumin (meBSA) or ovalbumin (OVA) with concurrent IL-1beta injections to the footpad to stimulate an immune response. Spontaneous remission occurs after 28 days, but arthritis flares in the original joints when re-stimulated with intraperitoneal meBSA or OVA. To track the site-specific persistence of TRM cells, we labelled synovial T cells using fluorescent reporter mice and IA injection of adeno-associated virus (AAV). To assess the importance of lymphocyte recruitment to an arthritis flare, we treated mice with FTY720, a sphingosine-1 phosphate receptor modulator that sequesters lymphocytes in lymphoid tissues, and evaluated joint inflammation after triggering a flare. Finally, to demonstrate the contribution of synovial TRM cells to the flare response, we locally depleted synovial T cells with a single IA injection of diphtheria toxin into mice with Lck-inducible diphtheria toxin receptors prior to triggering an arthritis flare.

Results: We found that synovial TRM cells persist in previously inflamed joints 8 months after remission and retained their capacity to trigger a flare in a site-specific manner. AAV-labelled TRM cells present in the synovium during remission did not migrate to the contralateral joint. TRM cells enabled joint inflammation by recruiting effector lymphocytes to the joint, and correspondingly localized depletion strongly blunted the capacity to flare arthritis.

Conclusion: Synovial TRM cells persist in arthritic joints and retain their capacity to trigger a site-specific flare after prolonged periods of remission. Our data suggest that synovial resident memory T cells can mediate joint-specific memory in inflammatory arthritis and trigger flares by recruiting circulating lymphocytes, suggesting local depletion of TRM cells as a potential therapeutic strategy.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/persistent-synovial-resident-memory-t-cells-mediate-arthritis-flares/