Background/Purpose: Programmed death protein 1 (PD-1) expressing T cells, including T follicular and T peripheral helper cells, are expanded in the circulation of individuals with rheumatoid arthritis (RA). Despite this, the origins of these cells and their functional role in RA remain poorly understood. To address this, we sought to investigate the genetic profiles of PD-1-expressing lymphocytes of the peripheral blood and synovial infiltrate of patients with early RA, and to characterise these cells in disease.

Methods: Isolated peripheral blood mononuclear cells (PBMCs) from patients with established RA (n=5) were sorted into CD4⁺/CD8⁺ PD-1⁺/^– populations by fluorescence activated cell sorting. mRNA was then isolated, converted into cDNA libraries, and subjected to total RNA sequencing using a NextSeq500. In conjunction with this, quantitative reverse-transcription PCR was used to support our findings. Finally, we assessed for alterations in CD4⁺PD-1⁺ and CD8⁺PD-1⁺ cell gene expression in synovial tissue (ST) biopsies (n=19) before and after six-month triple disease modifying anti-rheumatic drug (tDMARD) treatment.

Results: Proportions of CD4⁺ and CD8⁺ cells were expanded in the early RA synovial tissue (ST) compared with the peripheral blood. Comparisons of the gene signatures between CD4⁺PD-1⁺ vs. PD-1^– cells from early RA PBMCs identified significant upregulation of genes involved in the inflammatory response including IL21, CXCL13, and c-MAF, and in pathways including T helper-1 pathways, neuroinflammation signalling, and pathways involved in crosstalk between dendritic cells and natural killer cells. No significant differences in gene signatures between CD8⁺ PD-1⁺ vs. PD-1^– cells were observed. Additionally, analysis of gene signatures from early RA ST before and after six-month tDMARD treatment revealed down-regulation of the CD4⁺PD-1⁺ gene signatures (including genes such as PDCD1, CXCL13, and CTLA4) following treatment.

Conclusion: Our study suggests the pathogenic nature of CD4⁺ PD-1-expressing T cells in RA, and also reveals a mechanism through which tDMARDs exert their effect through influencing T cell populations in the synovial compartment. Furthermore, we identify factors associated with B cell help that are enhanced in the RA ST compared with PBMCs, highlighting the importance of these molecules in driving inflammation within the synovium.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/programmed-cell-death-protein-1-pd-1-expressing-cd4-t-cells-are-expanded-in-early-rheumatoid-arthritis-and-correlate-with-response-to-treatment/