CD4⁺CD8αlow T Cell Clonal Expansion Dependent on Costimulation in Patients With Rheumatoid Arthritis

Objective CD4 + CD8 + T cells are increased in patients with rheumatoid arthritis (RA). They are not only associated with joint erosions in established disease but are also present in the preclinical stages of RA. This study aims to further investigate their expansion in the context of T cell clonality in patients with RA, as well as their responsiveness to T cell–targeted treatment. Methods Single‐cell RNA (scRNA) and single‐cell T cell receptor (TCR) sequencing data were used to determine coreceptor expression and TCR sequences to assess the clonality of CD4 + CD8 + T cells in patients with RA (n = 3) and healthy controls (n = 2). Peripheral CD4 + CD8 + T cells and their subpopulations were measured in patients with RA (n = 53), patients with psoriatic arthritis (PsA; n = 52), and healthy donors (n = 50) using flow cytometry. In addition, changes in CD4 + CD8 + T cell frequency were prospectively observed in patients with RA receiving therapy with abatacept for 12 weeks. Results We observed an increase of CD4 + T cells expressing CD8α in patients with RA, both in comparison to patients with PsA and healthy controls. Clonality analysis revealed that these CD4 + CD8α low T cells are part of large T cell clones, which cluster separately from CD4 + CD8 − T cell clones in the scRNA sequencing (scRNA‐seq) gene expression analysis. Treatment with abatacept significantly reduced the frequency of peripheral CD4 + CD8α low T cells, and this was linked to reduction in disease activity. Conclusion In patients with RA, clonal expansion of CD4 + T cell culminates in the emergence of peripheral CD4 + CD8α low T cells, which are associated with disease activity and diminished upon abatacept treatment and could contribute to disease pathogenesis.