Role of T-bet B cells in rheumatoid arthritis - Although new treatments have improved outcomes in rheumatoid arthritis (RA), disability remains high, most patients have ongoing disease activity, and lasting remissions are rare. A major gap in the field is the elusive identity of pathogenic cells driving persistent inflammation and bone erosion. Our lab focuses on the identification of pathogenic B cell subsets in RA, which might drive persistent and aggressive disease. We reported that B cells promote bone erosion by RANKL/TNF-mediated differentiation of monocytes to osteoclasts (OCs) and TNF/CCL3- mediated inhibition of osteoblasts (OBs). Importantly, synovial B cells express much higher levels of these bone pathogenic factors. More recently, we identified a subset of B cells expressing the classic T cell lineage defining transcription factor T-bet enriched in the RA synovium and correlating with disease severity and the abundance of SLAMF7 pro-inflammatory monocytes. We find that synovial T-bet B cells express cytokines influencing OCs/OBs, SLAMF7, and the T- bet inducible chemokine receptor CXCR3. Remarkably, mouse B cells lacking T-bet did not activate OCs or inhibit OBs. Based on our results, the central goal of this proposal is to define how T-bet influences synovial B cell states, mediates B cell-driven bone effects on OCs/OBs, and coordinates B cell pathogenic functions in RA target tissue, contributing to joint erosion and synovial inflammation. We hypothesize that T-bet promotes pathogenic B cell functions in the RA synovium via acquisition of a pro-inflammatory cytokine/chemokine program that orchestrates CXCR3-dependent B cell migration to the synovium and enhances SLAMF7-dependent monocyte activation and bone erosion. We will use deeply characterized RA patient cohorts, high- resolution single cell transcriptomic and spatial analysis of joint target tissue, and novel animal models to track T bet B cells and selectively and conditionally delete T-bet in B cells of mice with collagen induced arthritis. The combination of preclinical and translational studies will facilitate the mechanistic interrogation of T-bet B cell functions in RA via 3 SAs: 1) Determine the mechanisms by which B cell T-bet promotes RA joint erosion; 2) Assess how T-bet B cells impact RA synovial monocyte activation; 3) Examine the role of T-bet in B cells during inflammatory- erosive arthritis in mice. By detailing the functional impact of T-bet B cells, innovative treatments targeting their activity may be a novel path towards preventing bone erosion and conferring lasting clinical remissions.
