Influenza continues to be a major source of illness in the United States, causing more than 35,000 deaths each year. And while most flu vaccines today are injected into the muscle, and are very effective at preventing severe illness, they do not consistently prevent infection in the nose and lungs. Nasal vaccines aim to solve this problem by targeting immunity at the site where viruses first enter, but their effectiveness has been inconsistent. Now, new research suggests that a previously overlooked group of immune cells may be critical players in improving this process.
This is published in Nature Immunology in the paper, “Monocyte-derived galectin-1hi cells provide innate immune help in the generation of functional memory CD8+ T cells.”
In the lungs, the specialized type of immune cell—a tissue-resident memory T cell—acts as a first line of defense at the site where viruses enter the body. “These cells are positioned right where infection begins, so they can react immediately and help limit viral spread,” said Minsoo Kim, PhD, professor of microbiology and immunology at University of Rochester Medicine. “They are a central goal for next-generation vaccine design because they provide fast, local protection in the respiratory tract.”
However, most current flu vaccines—especially those given by injection—do not reliably build strong immune memory in the airways, leaving a gap in protection against initial infection and transmission.
In the new study, researchers focused on how the immune system builds and maintains these protective memory T cells. They discovered that a subset of monocytes, a type of immune cell thought to be short-lived, can persist in the lungs for months after influenza infection. Instead of disappearing, they support the formation of immune memory by helping memory T cells survive and function in the lung.
More specifically, a “subset of newly recruited CCR2+ monocytes differentiated into memory-stage CCR2-tdTomato+ cells and persisted in the lung for more than four months after infection with the influenza virus.”
“Our work identified a long-lived monocyte-derived population in the lung that provides essential support for durable T cell immunity,” Kim said. “This challenges the traditional view that immune memory is driven only by T and B cells, and shows that innate immune cells also play a lasting role.”
The research also uncovered how these monocyte-derived cells communicate with T cells: they produce the galectin-1 protein, which helps activate and sustain tissue-resident memory T cells. When galectin-1 was added to an experimental nasal flu vaccine in mice, the immune response in the lungs became significantly stronger.
The authors write, “Memory-stage CCR2-tdTomato+ cells colocalized with lung CD8+ TRM cells and secreted galectin-1, which activated CD8+ T cells directly and enhanced transforming growth factor-β sensing.”
The finding opens the door to new vaccine strategies. “We identified galectin-1 as a powerful immune signal that can be used as a vaccine adjuvant to enhance mucosal immunity. This is a completely new approach for improving how vaccines work in the respiratory tract,” said Kim.
Beyond influenza, the findings may have implications for other respiratory viruses, including those that cause seasonal illness and pandemics. “We now see that innate immune cells are not just first responders—they can also shape long-term immune memory,” said Kim. “This opens up the possibility of designing vaccines that intentionally reprogram these cells to improve protection.”
Researchers are now working to develop more stable forms of galectin-1 that could be safely used as a vaccine additive. If these findings translate successfully to humans, they could reshape how respiratory vaccines are designed. Instead of focusing only on antibody responses or circulating immune cells, future vaccines may also target the long-term behavior of immune cells that live in the lungs themselves.
By harnessing this newly discovered “helper” population of immune cells, researchers hope to build vaccines that not only prevent severe disease but also stop infection earlier and more effectively at the point of entry.
