Background Systemic Lupus Erythematosus (SLE) is characterized by loss of tolerance towards nuclear antigens and uncontrolled activation of self-reactive T and B cells. Several studies have shown phenotypic and quantitative abnormalities of regulatory T cells (Treg) in SLE patients. In addition, impaired IL-2 production by T cells has been connected with SLE. Recently we have demonstrated that an acquired and therapeutically reversible IL-2 deficiency is responsible for the disruption of Treg homeostasis in a lupus mouse model.
Objectives In order to substantiate the rationale for an IL-2-based immunotherapy of human SLE we investigated whether CD4+Foxp3+CD127lo Treg of SLE patients display phenotypic and homeostatic abnormalities that are associated with IL-2 deficiency in analogy to murine lupus.
Methods Phenotype, frequency and proliferative status of CD4+Foxp3+CD127lo Treg and CD4+Foxp3- conventional T cell (Tcon) subsets in peripheral blood from 30 SLE patients and age-matched healthy controls were analyzed by 8-10 colour flow-cytometry. Two-tailed Mann-Whitney U test was used for statistical analysis between the SLE and the control group (p<0.05 is regarded as statistically significant).
Results The overall frequency of Foxp3+CD127lo Treg is significantly increased in SLE patients compared to healthy controls (p=0.003). In contrast, the percentage of CD25 expressing cells among Foxp3+CD127lo Treg is significantly reduced in SLE (p=0.003). The distribution of Treg subsets in SLE patients is shifted towards a memory phenotype with a significantly lower percentage of CD45RA+CCR7+ naive (p=0.001) and higher frequencies of CD45RA-CCR7- effector (p=0.022) and CD45RA-CCR7+ central memory (p=0.025) Treg. The percentage of proliferation, as determined by Ki67 expression, is increased in Treg from SLE patients in contrast to healthy controls (p=0.024). A significantly higher increase in Tcon proliferation however, results in a strongly reduced ratio of Treg proliferation versus Tcon proliferation in SLE patients (P=0.0004). Most proliferating Treg and Tcon belong to the memory/effector subset.
Conclusions Although an increased frequency of Foxp3+CD127lo Treg can be observed in SLE patients, the loss of CD25 expression and the predominance of Treg with a memory/effector phenotype suggest a profound disorder in Treg biology. In parallel, the decreased ratio between proliferating Foxp3+CD127lo Treg and Foxp3- Tcon indicates that the homeostatic balance between Treg and effector T cells is disturbed in SLE patients. Together, Foxp3+CD127lo Treg from SLE patients display phenotypic and homeostatic abnormalities that are very similar to those observed in lupus and IL-2-/- mice, suggesting an IL-2 deprivation of Treg also in human SLE.
Disclosure of Interest None Declared
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