Peripheral and site-specific CD4+CD28null T cells from Rheumatoid Arthritis patients show distinct characteristics

摘要

Proinflammatory CD4⁺CD28^null T cells are frequently found in the circulation of RA patients, but are less common in the rheumatic joint. In the present study we sought to identify functional differences between CD4⁺CD28^null T cells from blood and synovial fluid in comparison to conventional CD28 expressing CD4⁺ T cells. 44 RA patients, displaying a distinct CD4⁺CD28^null T cell population in blood, were recruited for this study and the methylation status of the IFNG locus was examined in isolated T cell subsets, and intracellular cytokine production (IFN-γ, TNF, IL-17) and chemokine receptor expression (CXCR3, CCR6 and CCR7) were assessed by flow cytometry on T cells from the two compartments. Circulating CD4⁺CD28^null T cells were significantly more hypomethylated in the CNS-1 region of the IFNG locus than conventional CD4⁺CD28⁺ T cells and produced higher levels of both IFN-γ and TNF after TCR crosslinking. CD4⁺CD28^null T cells from the site of inflammation expressed significantly more CXCR3 and CCR6 compared to their counterparts in blood. While IL-17A production could hardly be detected in CD4⁺CD28^null cells from the blood, a significant production was observed in CD4⁺CD28^null T cells from synovial fluid. CD4⁺CD28^null T cells were not only found to differ from conventional CD4⁺CD28⁺ T cells in the circulation, but we could also demonstrate that synovial CD4⁺CD28^null T cells showed additional effector functions (IL-17 co-production) as compared to the same subset in peripheral blood, suggesting an active role for these cells in the perpetuation of inflammation in the subset of patients having a CD28^null population.