Murine mesenchymal stem cells suppress T lymphocyte activation through IL-2 receptor α (CD25) cleavage by producing matrix metalloproteinases

Abstract

Mesenchymal stem cells (MSCs) are multipotent, non-hematopoietic stem cells that exhibit the capacity to inhibit the proliferation of a variety of immune cells. However, the underlying mechanisms of the immunosuppressive effects of MSCs are still obscure. Therefore, we attempted to identify the mechanisms underlying immunosuppression toward the activated T lymphocytes by MSCs in a murine model. In particular, we aimed to find possible factors derived from MSCs that drive this phenomenon. We found that T lymphocytes incubated with conditioned media of MSCs (MSC CM) entered into apoptosis and were subjected to cell cycle arrest during the course of activation, and these phenomena were accompanied by the reduction of IL-2 production. Specifically, matrix metalloproteinases (MMPs) derived from MSCs caused cleavage of IL-2 receptor α (CD25) from the surface of activated T cells, and as a consequence, IL-2 signaling in response to engagement of the IL-2 receptor (IL-2R) was downregulated. The inhibition of MMP activity in the MSC CM by GM6001 abrogated CD25 cleavage and restored IL-2 production from the activated splenocytes. However, the blockade of MMP activity could not fully restore the proliferative response and apoptosis of T cells altered by MSC CM. In conclusion, MSC-derived MMPs have a significant role in the suppression of IL-2 production through induction of CD25 cleavage and have a partial role in the suppression of T cell proliferation.