Peripheral and Site‐Specific CD 4 + CD 28 null T Cells from Rheumatoid Arthritis Patients Show Distinct Characteristics

Proinflammatory CD 4 + CD 28 null T cells are frequently found in the circulation of patients with rheumatoid arthritis ( RA ), but are less common in the rheumatic joint. In the present study, we sought to identify functional differences between CD 4 + CD 28 null T cells from blood and synovial fluid in comparison with conventional CD 28‐expressing CD 4 + T cells. Forty‐four patients with RA , displaying a distinct CD 4 + CD 28 null T cell population in blood, were recruited for this study; 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 ( CXCR 3, CCR 6 and CCR 7) were assessed by flow cytometry on T cells from the two compartments. Circulating CD 4 + CD 28 null T cells were significantly more hypomethylated in the CNS ‐1 region of the IFNG locus than conventional CD 4 + CD 28 + T cells and produced higher levels of both IFN ‐ γ and TNF after TCR cross‐linking. CD 4 + CD 28 null T cells from the site of inflammation expressed significantly more CXCR 3 and CCR 6 compared to their counterparts in blood. While IL ‐17A production could hardly be detected in CD 4 + CD 28 null cells from the blood, a significant production was observed in CD 4 + CD 28 null T cells from synovial fluid. CD 4 + CD 28 null T cells were not only found to differ from conventional CD 4 + CD 28 + T cells in the circulation, but we could also demonstrate that synovial CD 4 + CD 28 null T cells showed additional effector functions ( IL ‐17 coproduction) 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 CD 28 null population.