CD39-mediated IL-6 upregulation enhances T cell suppression of mesenchymal stem cells by inhibiting the IL-2 receptor.

초록

Mesenchymal stem cells (MSCs) have multipotent differentiation abilities and strong immunomodulatory effects, especially in suppressing T-cell responses. Among MSC-related immune regulation mechanisms, CD39, a surface protein that promotes adenosine production, has been widely studied. Although CD39 is involved in various immunomodulatory processes, its precise role within MSCs remains unclear. First, we noticed differences in CD39 levels among MSC populations. We then sorted cells to isolate MSCs with low and high CD39 expression. We found that the ability to suppress T-cells depended on CD39 levels, while CD73 levels stayed similar between the two groups. Next, we observed that CD39hi MSCs secreted more IL-6 than CD39lo MSCs when co-cultured with lymphocytes under CD3/CD28 stimulation. Additionally, CD39hi MSCs more effectively inhibited IL-2 receptor subunit expression on T cells than CD39lo MSCs, with a stronger suppression of the IL-2 receptor beta chain (CD122). Moreover, blocking IL-6 with neutralizing antibodies restored T-cell activation in the presence of MSCs. Conversely, adding recombinant IL-6 increased MSCs' suppression of T-cell proliferation, and IL-6 neutralization reversed the reduction in CD122 caused by IL-6. These findings suggest that CD39 in MSCs regulates IL-6 production, leading to lower IL-2 receptor expression and reduced T-cell activation. Finally, in a DSS-induced IBD mouse model, CD39hi MSCs demonstrated superior therapeutic effects compared to CD39lo MSCs, as evidenced by enhanced colon length and a lower disease activity index. Overall, these results highlight CD39 in MSCs as a fine-tuning regulator of T-cell suppression, pointing to its potential as a biomarker for MSC-driven immunosuppression.