Expansion of unusual CD4+ T cells in severe rheumatoid arthritis

Objective. The repertoire of T cells in patients with rheumatoid arthritis (RA) is characterized by clonal expansion of selected CD4+ T cells, which are autoreactive and lack the expression of the functionally important CD28 molecule, The goal of this study was to determine the contribution of these unusual lymphocytes to the disease process. Methods. RA patients (n = 108) and normal controls (n = 53) were examined for the expression of CD4+CD28- T cells by 2-color fluorescence-activated cell sorter analysis, Clinical data were ascertained by retrospective chart review. Results. The frequencies of CD4+CD28- T cells displayed a bimodal distribution, defining carriers and noncarriers in normal subjects and RA patients, In longitudinal studies, the noncarrier and carrier phenotypes were stable over time, Carriers of CD4+CD28- T cells accumulated in the RA population (64% versus 45%; P = 0.02), The expansion of CD4+CD28- T cells correlated with extraarticular involvement, but not with disease duration, antirheumatic treatment, or severity of joint destruction, The patient subsets with nodular disease (P = 0.02) and rheumatoid organ disease (P = 0.04) had the highest proportion of CD4+CD28- T cell carriers. The size of the CD4+CD28- compartment correlated with extraarticular progression of RA (P = 0.001 in nodular RA, P = 0.003 in rheumatoid organ disease). Conclusion. The bimodality of distribution of CD4+CD28- T cell frequencies is compatible with genetic control of the generation of these unusual T cells, In RA patients, CD4+CD28- T cells are not an epiphenomenon of the disease process, but predispose patients to developing inflammatory lesions in extraarticular tissues.