A team from the National Center for Cardiovascular Research (CNIC) has described a "checkpoint" in mitochondria—the cell's power plant—that allows dendritic cells, responsible for alerting the immune system, to efficiently activate T cells against viruses and tumors.
The work, published in the journal "Science Immunology," demonstrates that correcting the internal chemical imbalance caused by poor mitochondrial function in dendritic cells restores the immune cells' responsiveness, that is, their ability to defend the body against external agents. This finding could open the door to new strategies for enhancing cancer immunotherapy.
The researchers detail that the ability of dendritic cells to activate T cells depends on an unexpected mechanism: the correct state of the mitochondrial complex I, an essential element of mitochondria in these cells. This complex I acts as a "metabolic switch" essential for dendritic cells to convert virus fragments or tumor cells into effective immune signals and to intensely activate T cells.
The study, coordinated by David Sancho, from the CNIC, and Michel Enamorado, from the Icahn School of Medicine at Mount Sinai (USA), thus describes a new metabolic checkpoint that conditions the effectiveness of this "teaching" of the immune system.
"We have discovered that mitochondrial complex I acts as a true metabolic switch. Without its proper functioning, dendritic cells lose much of their ability to activate T cells to fight threats such as tumors or viruses," explains Sancho.
The co-first authors of the work, Sofía C. Khouili and Elena Priego (CNIC), emphasize that the activity of mitochondrial complex I is essential for dendritic cells to properly activate T cells. "When complex I functions poorly, dendritic cells have difficulty presenting enough antigen to T cells, which reduces their activation and their responsiveness to viruses or tumors," Khouili pointed out.
Along the same lines, Priego details that "the key lies in the increase of NADH with respect to NAD+ that appears when there is a deficiency of complex I. If we recover that chemical balance with pharmacological interventions, the ability of dendritic cells to activate T lymphocytes against viral infections or in anti-tumor responses is restored."
Sancho and Enamorado point out that, in certain scenarios, such as the tumor microenvironment, the mitochondrial function of dendritic cells can be compromised, which reduces their ability to activate T lymphocytes. "We identified the mitochondrial complex I in the dendritic cell as a key control point and demonstrated that correcting the internal chemical imbalance associated with its malfunction can restore the immune response in experimental models," they highlight.
These findings, they conclude, "show new avenues for enhancing vaccines and immunotherapies." The project has received funding from the Ministry of Science, Innovation and Universities through the State Research Agency and the NextGenerationEU/PRTR program of the European Union; from the Community of Madrid; from the Spanish Association Against Cancer (AECC); from Worldwide Cancer Research; from the CRIS Cancer Foundation and from the "la Caixa" Foundation.