Lower expression levels of the programmed death 1 receptor on CD4+CD25+ T cells and correlation with the PD-1.3A genotype in patients with systemic lupus erythematosus.

ABSTRACT

OBJECTIVE: A genetic polymorphism in the programmed death 1 (PD-1) gene encoding the coinhibitory PD-1 immunoreceptor, PD-1.3A, is associated with systemic lupus erythematosus (SLE). The aim of this study was to assess PD-1 receptor expression in patients with SLE, in comparison with relatives and unrelated healthy controls, and to identify correlations of lower expression levels of PD-1 receptor with the PD-1.3A genotype. METHODS: Patients with SLE, patients' relatives, and unrelated healthy control subjects from Iceland and Sweden were studied. Peripheral blood mononuclear cells (PBMCs) were stimulated with anti-CD3/anti-CD28, and PD-1 expression was analyzed by flow cytometry. PD-1.3A/G genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism analysis. RESULTS: PD-1 expression on PBMCs was induced after antibody stimulation, showing increases of 2.1-fold in SLE patients, 3.1-fold in relatives, and 5.1-fold in healthy controls. The frequency of PD-1+ cells was significantly lower in SLE patients compared with relatives and healthy controls. PD-1 expression on PD-1+ cells and on CD4+CD25+ T cells was significantly lower in SLE patients and relatives compared with healthy controls. PD-1 expression was significantly elevated on CD25(high) cells. Levels of PD-1 expression on CD25(high) and CD25(intermediate) cells were significantly lower in SLE patients compared with healthy controls. PD-1 was expressed on both FoxP3- and FoxP3+ cells. Lower expression of PD-1 was significantly correlated with the PD-1.3A/G genotype. CONCLUSION: The results demonstrate significantly lower PD-1 receptor expression in SLE patients and their relatives and reveal a significant correlation of lower PD-1 expression with the PD-1.3A allele. Thus, PD-1.3A may contribute to abnormalities in PD-1 receptor expression on CD4+CD25+ T cells in patients with SLE, providing support for an important role of the PD-1 pathway in SLE and, possibly, in other autoimmune diseases.