Modulation of CD28 expression with anti-tumor necrosis factor α therapy in rheumatoid arthritis

Objective. The immune system of patients with rheumatoid arthritis (RA) is characterized by the accumulation of CD4+ T cells deficient in CD28 expression and the up-regulation of tumor necrosis factor a (TNF alpha). Previous in vitro studies have shown that TNF alpha induces transcriptional silencing of the CD28 gene. Because reduced expression of CD28 in T cells compromises immunocompetence, we examined whether CD28 expression is reduced in patients with RA in vivo and whether the reduction is related to TNFa. Methods. Patients with RA and age-matched individuals were recruited. Peripheral blood mononuclear cells were stained for CD3, CD4, CD8, CD28, TNF receptor I (TNFRI), and TNFRII, and analyzed by quantitative flow cytometry. The number of CD28 and TNFR molecules was monitored in a subgroup of patients with RA undergoing treatment with anti-TNF alpha. Results. In addition to higher frequencies of CD28(null) T cells, patients with RA had significantly reduced numbers of CD28 and TNFRI molecules on CD4+, CD28+ T cells. Normal expression could be restored in vitro by overnight culture, suggesting that CD28 in patients was modulated by exogenous factors. In contrast, treatment with TNF alpha in vitro resulted in further down-regulation. CD28 expression was normalized in patients undergoing TNF alpha-neutralizing therapy. Conclusion. Overproduction of TNF alpha in RA induces a global down-regulation of CD28 in CD4+ T cells and may cause reduced sensitivity to costimulatory signals in T cell responses.