Background/Purpose: Regulatory T (Treg) cells play an important role in maintaining immunologic homeostasis. Abnormal Treg cells were found in some autoimmune diseases. Transferred natural Treg (nTreg) cells prevents some autoimmune disease but usually, fails to treat established diseases. Several studies demonstrated that natural CD4+CD25+ Foxp3+ Treg (nTreg) could be transdifferentiated into IL-17A-producing cells and lost its function in the presence of pro-inflammatory cytokines. Given IL-6 is an important inflammatory cytokine and IL-6 binds to its receptor (CD126) to exert functional role,  whereas some nTreg cells express CD126, we hypothesize that CD126- Foxp3+ cell subsets could be more stable and functional in the inflammatory condition.

Methods: Flow cytometry were used to analyze CD126 expression on nTreg from collagen induced collagen-induced arthritis (CIA). CD126+ and CD126- nTreg were sorted from CIA mice and analyzed the transcript difference via RNA-sequence. These two subsets were cultured in the presence of IL-6 to determine the stability.  Moreover, we transferred these two subsets into the established colitis model to analyze the function and stability of CD126+ and CD126- nTreg in vivo. Results were analyzed by using Graphpad Prism 7.0 software. Student t- test were used to assess statistical significance between two groups and one-way ANOVA was used to assess statistical significance among multi-groups.  p values less than 0.05 were considered a statistically significant difference.

Results: Compared to normal mice, the proportion of CD126+ nTreg from CIA mice was significantly higher.  CD126- nTreg cells express higher immunosuppressive molecule and present stronger function than CD126+ nTreg not only in the normal condition but also in the presence of IL-6. Moreover, CD126- nTreg was stable while CD126+ nTreg lost Foxp3 expression and trans-differentiated into IL-17A producing cells in the presence of IL-6. Impaired IL-6 signaling in CD126- nTreg was the primary mechanism responsible for the stability, 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- Tregs is more effective than CD126+ Tregs when transferred to treat colitis model.

Conclusion: CD126- nTreg cells present stronger function and stability even under inflammatory conditions than CD126+ nTreg cells. Our results suggest that manipulation of CD126- nTreg might be a novel strategy for the treatment of autoimmune diseases.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/cd126-negative-cd4foxp3-cell-represents-a-superior-treg-subset-in-treating-autoimmune-diseases/