Skewed distribution of proinflammatory CD4+CD28null T cells in rheumatoid arthritis

Expanded populations of CD4(+) T cells lacking the costimulatory molecule CD28 (CD4(+)CD28(null) T cells) have been reported in several inflammatory disorders. In rheumatoid arthritis, increased frequencies of CD4(+)CD28(null) T cells in peripheral blood have previously been associated with extraarticular manifestations and human cytomegalovirus (HCMV) infection, but their presence in and contribution to joint manifestations is not clear. In the present article we investigated the distribution of CD4(+)CD28(null) T cells in the synovial membrane, synovial fluid and peripheral blood of RA patients, and analysed the association with erosive disease and anti-citrullinated protein antibodies. CD4(+)CD28(null) T cells were infrequent in the synovial membrane and synovial fluid, despite significant frequencies in the circulation. Strikingly, the dominant TCR-V beta subsets of CD4(+)CD28(null) T cells in peripheral blood were often absent in synovial fluid. CD4(+)CD28(null) T cells in blood and synovial fluid showed specificity for HCMV antigens, and their presence was clearly associated with HCMV seropositivity but not with anti-citrullinated protein antibodies in the serum or synovial fluid, nor with erosive disease. Together these data imply a primary role for CD4(+)CD28(null) T cells in manifestations elsewhere than in the joints of patients with HCMV-seropositive rheumatoid arthritis.