Transfer of mesenchymal stem cell mitochondria to CD4+ T cells contributes to repress Th1 differentiation by downregulating T-bet expression

作者：Waseem Akhter, Jean Nakhle, Loı̈c Vaillant, Geneviève Garcin, Cécile Le Saout, Matthieu Simon, Carole Crozet, Farida Djouad, Christian Jørgensen, Marie‐Luce Vignais, Javier Hernández · 发表于：Stem Cell Research & Therapy · 年份：2023 · DOI：10.1186/s13287-022-03219-x · 被引用次数：47 · 研究领域：Mesenchymal stem cell research、Immune cells in cancer、Immune Cell Function and Interaction

Abstract Background Mesenchymal stem/stromal cells (MSCs) are multipotent cells with strong tissue repair and immunomodulatory properties. Due to their ability to repress pathogenic immune responses, and in particular T cell responses, they show therapeutic potential for the treatment of autoimmune diseases, organ rejection and graft versus host disease. MSCs have the remarkable ability to export their own mitochondria to neighboring cells in response to injury and inflammation. However, whether mitochondrial transfer occurs and has any role in the repression of CD4 + Th1 responses is unknown. Methods and results In this report we have utilized CD4 + T cells from HNT TCR transgenic mice that develop Th1-like responses upon antigenic stimulation in vitro and in vivo. Allogeneic bone marrow-derived MSCs reduced the diabetogenic potential of HNT CD4 + T cells in vivo in a transgenic mouse model of disease. In co-culture experiments, we have shown that MSCs were able to reduce HNT CD4 + T cell expansion, expression of key effector markers and production of the effector cytokine IFNγ after activation. This was associated with the ability of CD4 + T cells to acquire mitochondria from MSCs as evidenced by FACS and confocal microscopy. Remarkably, transfer of isolated MSC mitochondria to CD4 + T cells resulted in decreased T cell proliferation and IFNγ production. These effects were additive with those of prostaglandin E2 secreted by MSCs. Finally, we demonstrated that both co-cultur...