CD126 negative regulatory cells represents a superior Treg subset in treating autoimmune diseases

Treg cells play an important role in maintaining immunologic homeostasis. Abnormal Treg were found in some autoimmune diseases. Infusion of natural Treg (nTreg) prevents some autoimmune disease but usually fails to treat established diseases. Several studies demonstrated nTreg could be transdifferentiated into Th17 cells and lost its function under inflammatory condition. Given IL-6 is an important inflammatory cytokine and it binds to its receptor (CD126) to exert functional role, whereas nTreg express CD126, we hypothesize that CD126− Foxp3+ cell subsets could be more stable and functional in the inflammatory condition. CD126+ and CD126− nTreg were sorted from collagen-induced arthritis (CIA) and then were analyzed for transcript difference via RNA-sequence. They were cultured in the presence of IL-6 to determine the stability and function following a colitis model in vivo. Compared to normal mice, the proportion of CD126+ nTreg in CIA was significantly higher. CD126− nTreg express higher immunosuppressive molecules and present stronger function than CD126+ nTreg in both normal condition and presence of IL-6. Moreover, CD126− nTreg was stable while CD126+ nTreg lost Foxp3 expression and trans-differentiated into Th17 in the presence of IL-6. In addition, CD126− nTreg exhibited reduced Hif-1a and glucose transporter 1(Slc2a1) expression, which are two key regulators of glycolytic metabolism and play an important role in the balance of Th17 and Treg. Finally, CD126− Treg more potent treat colitis compared to control. We show CD126− nTreg present stronger function and stability under inflammatory conditions Our results suggest that manipulation of CD126− nTreg might be a novel strategy for the treatment of autoimmune diseases.