Reprogramming CD8+ T cell metabolism and fate by MSC mitochondrial transfer

• Applicant: Professor Dr. Luca Gattinoni
• Subject Area: Immunology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 499380536

CD8+ T cells play an important role in immunity by clearing cells infected by pathogens and cancer cells and by providing long-term protection against disease recurrence. Key regulators of CD8+ T cell function are mitochondria, organelles within cells that are responsible for generating the majority of cells’ energy. Recent evidence has demonstrated that mitochondria within a cell are not fixed, but can travel from one cell to another through a process known as ‘mitochondrial transfer’. We have found that mesenchymal stromal cells (MSC), a heterogeneous mesenchymal cell population with broad immunomodulatory activity, can donate mitochondria to CD8+ T cells in vitro to enhance their metabolic fitness and capacity to mediate antitumor immunity upon adoptive transfer. The following research proposal explores the role of MSC mitochondrial transfer in boosting CD8+ T cell metabolism and rewiring CD8+ T cell fate in vivo to promote the establishment of long-lived memory cells against pathogens. The project also aims to unravel the mechanisms and immunological cues that drive mitochondrial transfer and to exploit this knowledge to artificially increase mitochondrial transfer for therapeutic applications. The findings from these studies will redefine our understanding of how MSC and stromal niches control the generation and maintenance of immunological memory. The new biology discovered will have major implications for the development of novel vaccination strategies against pathogens and foster radical innovation in the design of new T cell-based cancer immunotherapies.

• DFG Programme: Reinhart Koselleck Projects