The TGF-β/miR-31/CEACAM1-S axis inhibits CD4+ CD25+ Treg differentiation in systemic lupus erythematosus.

Defects causing concomitant loss of CD25 expression in Tregs have been identified in systemic lupus erythematosus (SLE). However, the cause of this deficiency is not fully understood. CEACAM1, an immune co-receptor, contributes to general T-cell function and activation. Our previous study revealed CEACAM1 expression was up-regulated in PBMCs from SLE patients. However, its role remains unclear. Herein, we confirmed CEACAM1, especially CEACAM1-S was up-regulated in PBMCs from SLE patients. CEACAM1-S over-expression inhibits CD4+ CD25+ Tregs differentiation, whereas knock-down of CEACAM1 had the opposite effect in vitro. CEACAM1-S is the target of miR-31. MiR-31 mimic inhibits CEACAM1 expression and enhance CD4+ CD25+ Tregs differentiation, which was reversed by CEACAM1-S over-expression. Moreover, the circulating TGF-β level was up-regulated in SLE patients and TGF-β reduced miR-31expression via enhancing NF-КB activity. Importantly, CEACAM1 and TGF-β mRNA levels were down-regulated, while the miR-31 level and abundance of CD4+ CD25+ Tregs were increased in inactive patients compared with that in active SLE patients. In addition, CEACAM1-S expression was positively correlated with SLEDAI score, while CD4+ CD25+ Tregs abundance and miR-31 level were negatively correlated with SLEDAI score. In conclusion, reduced activity of miR-31 by TGF-β, via the inhibition of NF-КB, acted to inhibit the differentiation of CD4+ CD25+ Tregs by directly targeting CEACAM1-S and promote autoimmunity.