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In vivo functions of nuclear envelope rupture and antiviral specialization in dendritic cells

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Improving our understanding of the body’s immune response

To uncover more about how immune responses work, the DCBIO project explored the minutiae of dendritic cells. The work could help scientists better understand ageing and deterioration of the immune system.

Health

“Broadening our knowledge of how the immune system works is critical to allowing the development of creative therapeutic strategies to address unmet medical needs,” says Nilushi De Silva, Marie Skłodowska-Curie research fellow at the Institut Curie France, and lead researcher on the DCBIO project. DCBIO aimed to reveal novel mechanisms that regulate the immune system. The team investigated whether the nuclear envelope, which is the membrane surrounding the nucleus, has a role in immune system regulation, and explored the division of antiviral labour among dendritic cells. Dendritic cells are critical to immune responses against viruses in mammal systems, working at the border between innate and adaptive immunity. They work like watchmen in the body, seeking out and presenting invading viral antigens to other killer cells which then destroy the invader. Researchers had previously observed that in physically constricted environments in lab settings, migrating dendritic cells can result in the nuclear envelope breaking open on some cells. “This finding was surprising as healthy cells usually only open their nuclear envelope immediately before division. Indeed, a nuclear envelope breach outside this context could be highly dangerous as it could lead to DNA damage caused by the entrance of antiviral enzymes, or spark unwanted immune responses,” De Silva explains. The immune consequences of nuclear envelope rupture in vivo are unknown and were investigated in the DCBIO project.

Nuclear efficiencies

The team investigated the impact of nuclear envelope modulation on the immune system by analysing a range of immune cell populations in mice. They identified a nuclear envelope mutant with a striking loss of an important immune population residing within the lung. This phenotype was associated with DNA damage and lung pathology. “Interestingly, we believe this phenotype also mimics some aspects of natural ageing resulting in an aged immune population residing within the body of a young mouse. This work has implications for understanding natural ageing mechanisms within the immune system,” notes De Silva. Immunosenescence, the deterioration of the immune system, and immune system ageing are not well understood, so understanding these mechanisms further should reveal opportunities for new treatment interventions. “We believe our study may also reveal important markers of immunosenescence that could have clinical applications for monitoring ageing within the immune system,” adds De Silva.

Personal journey

De Silva is pleased to be able to contribute to our understanding of these fundamental medical processes, to help scientists reveal new therapeutic opportunities in the future. She explains how the Horizon 2020 grant was crucial. “Without this long-term support, it would not have been possible for me to explore these bold ideas,” De Silva notes. “I am proud that I was able to train as a scientist and work on cutting-edge questions. Sitting in my first biology class in high school, the thought of becoming an active scientist seemed like a very distant possibility.” The next steps are to conduct further research into the links between nuclear protection provided by the nuclear envelope and ageing in the lung.

Keywords

DCBIO, dendritic cells, immune system, lung, immunosenescence, research

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