Background/Purpose: Rheumatoid arthritis (RA) is a systemic autoimmune disease featured with recurrent inflammation in the same joints, a characteristic termed joint-specific memory. We previously demonstrated that joint-specific memory in arthritis is mediated by resident memory T (TRM) cells in the synovium. TRM cells remain in the synovium of previously inflamed joints and activation of TRM cells can drive recurrent arthritis flare. However, the factors that mediate the persistence of TRM cells in the synovium are unclear. Here, we investigate the role of CD49a in the retention and survival of TRM in synovial tissue.

Methods: We generated synovial organoids with CD8 memory T cells isolated from peripheral blood mononuclear cells, fibroblast-like synoviocytes (FLS) isolated from RA synovium, and human umbilical vein endothelial cells (HUVEC) encapsulated in Matrigel. TRM cells form within the synovial organoid after 3 weeks of culture. To evaluate whether CD49a mediates binding of TRM cells to FLS, isolated TRM cells were incubated with isotype or CD49a neutralizing antibodies, then added to a microfluidic slide (μ-Slide I Luer) seeded with FLS. The strength of cell binding was assessed through live cell imaging of bound TRM cells under increasing velocities of laminar flow. Cell survival was assessed in CD49a positive TRM cells through viability dye and Annexin V staining in cells remaining within the synovial organoids and those that migrated out of the Matrigel. Cell proliferation was assessed in CD49a positive TRM cells through intracellular staining for Ki67.

Results: We found that TRM cells incubated with CD49a neutralizing Ab had lower binding affinity to FLS. Further, CD49a positive TRM cells had less cell death compared to CD49a negative TRM cells, and viability of TRM cells also increased in cells remaining within the synovial organoids. Moreover, there is increased Ki67 expression in CD49a positive TRM cells compared to CD49a negative TRM cells at 21 days of culture.

Conclusion: We showed that CD49a contributes to binding of TRM cells to FLS. Further, CD49a positive TRM cells have increased viability particularly within the organoid structure and a higher proliferative capacity even after 21 days of culture, suggesting a possibility for self-renewal. Our findings implicate CD49a in the persistence and survival of TRM cells in synovial tissue. Targeting TRM cell anchoring could provide a novel therapeutic approach to joint-specific memory and chronic arthritis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/cd49a-contributes-to-binding-and-survival-of-synovial-resident-memory-t-cells/