Proinflammatory CD20⁺CD3⁺ T cells as a potential driver of macrophage reprogramming in rheumatoid arthritis

CD20⁺CD3⁺ T cells, a distinct immune cell population implicated in immune responses, contribute to the development of multiple diseases. However, their role in RA progression, particularly their potential to drive the reprogramming of monocyte-derived macrophages toward a pathogenic state akin to synovial tissue macrophages (STMs), remains unclear.

Single-cell RNA sequencing and flow cytometry were conducted on RA patients and healthy controls. CD14⁺ monocytes isolated from the peripheral blood of RA patients were co-cultured with CD20⁺CD3⁺ T cells to study their effect on monocyte differentiation. A collagen-induced arthritis (CIA) model was used to assess the pathogenic potential of transferring CD20⁺CD3⁺ T cells.

RA patients have a higher frequency of CD20⁺CD3⁺ T cells than healthy controls, with single-cell analysis showing increased ANXA1-FPR1 interaction between these T cells and monocytes. ANXA1⁺CD20⁺CD3⁺ T cells and FPR1⁺ monocytes are more prevalent in RA patients. The role of ANXA1-FPR1 signaling is supported by a higher number of CD48⁺ cells in the MerTK‾CD206‾ macrophages subset after co-culture with CD20⁺CD3⁺ T cells. CIA mice administered CD20⁺CD3⁺ T cells exhibited more severe arthritis and more proinflammatory STMs infiltration than CIA controls.

CD20⁺CD3⁺ T cells exacerbate synovitis and drive RA progression by promoting the recruitment and pro-inflammatory differentiation of monocyte-derived macrophages (particularly the CD48⁺MerTK‾CD206‾ subset) via ANXA1-FPR1 signaling, representing a potential therapeutic target.