CD4+CD8αlow T cells in rheumatoid arthritis are clonally expanded and dependent on co-stimulation.

Objectives: 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 pre-clinical 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-(sc)RNA- and scTCR-sequencing data were used to determine co-receptor expression and T cell receptor sequences to assess clonality of CD4⁺CD8⁺ T cells in RA (n=3) patients and healthy controls (n=2). Peripheral CD4⁺CD8⁺ T cells and their subpopulations were measured in patients with RA (n=53), PsA (n=52) and healthy donors (n=50) using flow cytometry. In addition, changes in CD4⁺CD8⁺ T cell frequency were prospectively followed in RA patients receiving therapy with abatacept for 12 weeks.

Results: We observed an increase of CD4⁺ T cells expressing CD8α in RA patients, both in comparison to PsA patients and to 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-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 RA, clonal expansion of CD4⁺ T cell clones culminates in the emergence of peripheral CD4⁺CD8α^low T cells, which are associated with disease activity and diminished upon abatacept treatment, and which could contribute to disease pathogenesis.