Mitochondrial transfer from MSCs to T cells induces Treg differentiation and restricts inflammatory response

Abstract

Mesenchymal stem cells (MSCs) have fueled ample translation for the treatment of immune‐mediated diseases. They exert immunoregulatory and tissue‐restoring effects. MSC‐mediated transfer of mitochondria (MitoT) has been demonstrated to rescue target organs from tissue damage, yet the mechanism remains to be fully resolved. Therefore, we explored the effect of MitoT on lymphoid cells. Here, we describe dose‐dependent MitoT from mitochondria‐labeled MSCs mainly to CD4 + T cells, rather than CD8 + T cells or CD19 + B cells. Artificial transfer of isolated MSC‐derived mitochondria increases the expression of mRNA transcripts involved in T‐cell activation and T regulatory cell differentiation including FOXP3, IL2RA, CTLA4, and TGFβ1, leading to an increase in a highly suppressive CD25 + FoxP3 + population. In a GVHD mouse model, transplantation of MitoT‐induced human T cells leads to significant improvement in survival and reduction in tissue damage and organ T CD4 + , CD8 + , and IFN‐γ + expressing cell infiltration. These findings point to a unique CD4 + T‐cell reprogramming mechanism with pre‐clinical proof‐of‐concept data that pave the way for the exploration of organelle‐based therapies in immune diseases. image This study reveals that MitoT directly shapes the immune response by inducing Tregs, which could be potentially used as a therapy for autoimmune diseases such as GVHD. Mitochondria are transferred from MSCs to CD4 + T cells. Mitochondrial transfer promotes Treg differentiation. Transplantation of mitochondria recipient human T cells alleviates inflammatory response and tissue damage in GVDH and SLE disease models.