Background/Purpose: Prior to the onset of clinically apparent inflammatory arthritis (IA)/synovitis (clinical RA), ACPA+ ‘at-risk’ individuals (ARI) show alterations in the abundance of effector T cell subsets in the peripheral circulation. However, it remains unclear which T cell subsets define the progression to clinical RA. A population of central memory CD4 T cells expanded over time as ACPA+ ARI progressed to clinical RA (termed ‘converters’). In this study, we investigated the molecular phenotype of this expanding memory T cell population in converters.

Methods: We conducted a longitudinal analysis of peripheral blood mononuclear cell (PBMC) transcriptomes obtained by scRNA-seq. We performed linear mixed effects longitudinal modeling on samples from ACPA+ participants over a period of 2 years prior to the onset of clinical RA (n=13 converters; n=61 samples; mean 4.7 samples per converter; Table 1). These samples were from a prospective longitudinal cohort study of ACPA+ individuals without baseline IA/synovitis. Cell-cell communication analyses to infer ligand-receptor interactions and downstream gene expression changes were performed using Liana and NicheNet.

Results: A memory CD4 T cell population that expanded almost 2-fold over time from baseline to conversion (FDR< 0.05) expressed PD1, ICOS, CXCR5 and KLRB1 transcripts, exhibited a transcriptionally activated state (P< 0.05) and were enriched for a published transcriptional signature of Tfh/Tph cells from RA synovial tissue (P< 0.01; Zhang 2019 Nature Immunol). Using an independent trimodal single cell validation dataset (Thomson 2023 Nature Immunol), we identified a CD4 memory population that expressed a similar PD1+ ICOS+ CXCR5+ KLRB1+ transcriptional signature. Notably, this population had the highest surface protein expression of PD-1 and ICOS, along with high expression of KLRB1 protein. We inferred key receptor-ligand communication between two lymphocyte populations that expanded as converters progressed to clinical RA: (1) the memory CD4 T cell population; and (2) CD27- TBX21+ atypical B cells. Potential receptor-ligand complexes included CD40LG-CD40, CD86-CD28, and SEMA4D-CD72, and was supported by downstream changes in gene expression following receptor-ligand interactions reported in both these populations.

Conclusion: These results suggest the increased population of central memory CD4 T cells in the peripheral blood of converters approaching transition to clinical RA is associated with changes in activated T cells with a B cell helper phenotype. This memory population could be similar to Tph cells found to be clonally expanded in RA synovium, but also shares features of Th17 cells, suggesting they could produce pro-inflammatory mediators that participate in disease pathogenesis. These findings are supported by inferred bidirectional signaling between these memory CD4 T cells and atypical B cells during progression to clinical RA. Our findings provide key insights into adaptive immune mechanisms that contribute to the progression from an at-risk state to clinical RA, and may suggest targets for early preventive intervention or biomarkers for RA prevention trials.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/potentially-pathogenic-memory-cd4-t-cells-with-a-b-cell-helper-phenotype-expand-in-acpa-individuals-during-progression-to-rheumatoid-arthritis/