T-cell specific defect in expression of the NTPDase CD39 as a biomarker for lupus

Regulatory T cells (T_regs) are critical for maintenance of peripheral tolerance via suppression of T-cell responses, and absence of T_regs results in autoimmunity. The role of aberrations in the T_reg pool for the development of systemic lupus erythematosus (SLE, lupus) remains uncertain. T_reg-mediated generation of adenosine, dependent on the ectonucleotidase CD39, is an important mechanism for suppression of T-cell responses. We tested whether decreases in numbers of T_regs, and specifically CD39-expressing T_regs, are associated with human lupus. We studied 15 SLE patients, six patients with rheumatoid arthritis (RA) and 24 healthy controls. T_reg phenotypic markers, including CD39 expression, were studied by flow cytometry. Varying numbers of sorted T_regs cells were co-cultured with responder T (T_resp) cells, with proliferation assessed by ³H-thymidine incorporation. The proportion of T_regs as defined by Foxp3⁺ CD25^+high CD127^−/low was similar in lupus and control populations. CD39-expressing T_regs comprised 37 ± 13% of the T_reg population in healthy controls and 36 ± 21% in lupus subjects using nonsteroidal immunosuppressants to control active disease, but was nearly absent in five of six lupus subjects with minimally active disease. In contrast to healthy controls and lupus subjects without the CD39 defect, in SLE subjects with the CD39 defect, adenosine-dependent T_reg-mediated suppression was nearly absent. These results suggest that functional defects in T_regs, rather than reduced T_reg numbers, are important for the loss of peripheral tolerance in lupus. Presentation of this defect may serve as a biomarker for untreated disease.