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

Regulatory T cells (Tregs) are critical for maintenance of peripheral tolerance via suppression of T-cell responses, and absence of Tregs results in autoimmunity. The role of aberrations in the Treg pool for the development of systemic lupus erythematosus (SLE, lupus) remains uncertain. Treg-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 Tregs, and specifically CD39-expressing Tregs, are associated with human lupus. We studied 15 SLE patients, six patients with rheumatoid arthritis (RA) and 24 healthy controls. Treg phenotypic markers, including CD39 expression, were studied by flow cytometry. Varying numbers of sorted Tregs cells were co-cultured with responder T (Tresp) cells, with proliferation assessed by 3H-thymidine incorporation. The proportion of Tregs as defined by Foxp3+ CD25+high CD127−/low was similar in lupus and control populations. CD39-expressing Tregs comprised 37 ± 13% of the Treg 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 Treg-mediated suppression was nearly absent. These results suggest that functional defects in Tregs, rather than reduced Treg numbers, are important for the loss of peripheral tolerance in lupus. Presentation of this defect may serve as a biomarker for untreated disease.

► Adenosinergic pathway mediated by CD39 is critical in regulatory T (Tregs) cell function.
► We tested whether decreased numbers of Tregs, and specifically CD39-expressing Tregs, are associated with human lupus.
► CD39 defect observed in SLE with minimally active disease is a pan-T cell defect and not limited to the Treg subset.
► The defect in CD39 expression by both Tregs and non-Tregs is not observed in patients with non-steroidal therapy.
► The CD39 defect may be useful as a biomarker for early detection of disease, before onset of clinical symptoms.