Abstract
The primary role of T lymphocytes is to protect the body against infections. Cytotoxic CD8+ T lymphocytes eliminate infected cells by secreting inflammatory cytokines, such as interferon-γ (IFN-γ). This process can malfunction, contributing to autoimmune diseases, graft rejection, or graft-versus-host disease (GvHD). In recent years, cell therapies aimed at limiting these undesirable responses have garnered increasing interest. Mesenchymal stem cells (MSCs) possess strong immunosuppressive properties. In an inflammatory context, MSCs can reduce the proliferation and activation of antigen-responsive CD8+ T lymphocytes. They exert this effect by secreting anti-inflammatory cytokines and soluble factors that modulate T cell differentiation. A remarkable feature of MSCs is their ability to transfer mitochondria to other cells through nanotubes or extracellular vesicles. However, the role of this mitochondrial transfer in the immunosuppression of CD8+ T lymphocytes remains unknown. We addressed this question using a transgenic mouse model for autoimmune diabetes and allogeneic bone marrow-derived MSCs in vitro and in vivo. Our results show that allogeneic MSCs reduce the expansion, acquisition of effector phenotype, and effector function of activated CD8+ T cells during in vitro co-culture. We observed that during the interaction between CD8+ cells and MSCs, which leads to immunosuppression, MSCs transfer mitochondria to CD8+ cells. This mitochondrial transfer inhibits the proliferation and IFN-γ production by effector CD8+ T cells, thereby contributing to the overall suppressive effect of MSCs. Additionally, MSC mitochondria and PGE2 have additive effects in inhibiting CD8+ T cell expansion. Finally, we demonstrated that MSCs and MSC mitochondria prevent the increased expression of key transcription factors, T-bet and Eomes, during the activation of cytotoxic CD8+ cells.