Scientists at Cincinnati Children’s Hospital have taken a deeper look at how our immune systems change with age, and their findings could help to make flu vaccines much more effective for older people. The results of the team’s studies, published in Science Advances, suggest that rather than becoming weaker, the immune system in the elderly is actively suppressed by the activity of a group of immune cells that the researchers have called interleukin 10-producing T follicular helper (Tfh 10) cells, and that this suppression is reversible. The study data indicated that removing this immune system suppression could trigger much stronger response to vaccination in the elderly. And – although far more research will be needed – it also appears possible to boost vaccine power by managing Tfh 10 cells in a way that avoids disrupting the useful roles the cells play in fending off other types of disease.

“These Tfh10 cells accumulate dramatically in our bodies as we age, and they have the effect of making older individuals less responsive to invading pathogens and less responsive to vaccines,” explained corresponding author David Hildeman, PhD, Interim Director, Division of Immunobiology. “The age-related variation in response to vaccines is a huge issue. The current influenza vaccine is roughly 90% protective in young people, but only about 30% effective in the elderly.” Hildeman is corresponding author of the team’s published paper, which is titled, “IL-10-producing Tfh cells accumulate with age and link inflammation with age-related immune suppression.”

Aging is associated with what the authors say is “profound immune dysfunction,” one of the results of which is a decline in vaccine responsiveness. This has previously been attributed to irreversible, age-related defects in the immune system, which also links to other age-related health issues. “Declining adaptive immune function in the elderly leads to increased risk and severity of infection, poorer control of cancer, and impaired responses to vaccination,” the investigators wrote.

Aging is also characterized by persistent low-grade immune activation – so-called “”inflammaging – which is implicated in processes that may lead to Alzheimer’s disease and cardiovascular diseases, and which is paralleled by high levels of interleukin-6 (IL-6). “High levels of circulating, proinflammatory interleukin-6 (IL-6) are associated with increased morbidity and mortality among older individuals,” the team noted. Paradoxically, and alongside this age-related increase in inflammaging is the recent observation that serum levels of IL-10, which is a potent anti-inflammatory mediator, are also increased in the elderly.

Scientists at Cincinnati Children’s have been studying the intricate details of the immune system for decades. Since the 1950s and the introduction of the Sabin oral polio vaccine, the medical center has been a leader in vaccine research – including working every year to help update influenza vaccine formulas and most recently recruiting thousands of people to test potential vaccines against COVID-19. Their newly reported studies indicate that while interleukin-6 (IL-6) acts as a force that contributes to this low-grade state of aging-related immune activation inflammaging, the body effectively fights the high levels of IL-6 by producing IL-10. “At first glance, the increased levels of IL-10 seem counterintuitive to the well-documented increased inflammation in aging,” the researchers noted. “However, the concept that both increases in both pro- and anti-inflammatory cytokines can coexist has been known for many years … these increases in both pro- and anti-inflammatory cytokines likely coexist as part of a feedback loop in which proinflammatory responses elicit an anti-inflammatory response.”

The team’s results thus point to a number of forces that act against each other as our immune systems respond over and over to infections, and suggest that the balance of these elements changes as we age, with certain types of cells building up over the years to become more like harmful clutter instead of useful weapons. Repeated cycles of response and counter-response result in an interleukin arms race that often leaves older bodies with excess levels of both IL-6 and IL-10. “… our data suggest that IL-10 production is a feedback mechanism to dampen, but not ameliorate, IL-6–driven inflammaging,” they wrote. “While there have been many associations between inflammaging and immune suppression, our data show a novel linkage between these two age-related phenomena …”

Undesired excessive Interleukin-10 (IL-10) production in aged mice comes primarily from Tfh cells, according to new findings published in Science Advances. This chart shows that when these cells are stimulated with IL-21, the percentage of IL-10 producing cells rises to 21% in older mice, but just to 9% in younger mice. [Cincinnati Children’s]

Importantly, the scientists were able to pinpoint the origin of the undesirable levels levels of IL-10. They conducted dozens of different experiments to rule out competing ideas. The studies traced excess IL-10 production to the cell type they dubbed Tfh 10. Then, in mouse models, they showed that simple blockade of IL-10 at the time of vaccination could restore the antibody response nearly to the level of young animals. “Our data suggest that, instead of enhancing proinflammation, transient blockade of IL-10 could be a novel strategy to enhance vaccine responses in the elderly and, due to its transient nature, is unlikely to have untoward effects on autoimmunity, cardiovascular disease, or frailty,” the co-authors stated.

The newly reported studies, in mice, were carried out by the Cincinnati Children’s team in collaboration with scientists at the University of Cincinnati, and colleagues in Germany, Alabama, and Indiana. “These findings are the result of five years of work stemming from a long-standing collaboration between my lab and Dr. Claire Chougnet’s lab, contributions from several faculty-level scientists, and particularly the hard work of one amazing former graduate student, Dr. Maha Almanan,” Hildeman said. Of particular interest, the team also found accumulation of Tfh10 cells in elderly humans. “Thus, in agreement with our data from mice, Tfh10 cells accumulate in aged humans. These findings may explain the well-known age-related impairment in vaccine responsiveness in the elderly,” the authors wrote.

Their therapeutic approach may feasibly increase vaccine efficacy in the elderly, potentially reducing deaths caused by yearly influenza outbreaks, which have claimed 12,000 to 61,000 American lives per year since 2010, according to the Centers for Disease Control and Prevention. So could the same strategy be used to boost response to future COVID-19 vaccines? “Yes, it could,” said Hildeman. “As the elderly do not respond well to multiple vaccines, it is highly likely that the elderly will also not respond as well as the young to new vaccines, either for COVID19 or other emerging pathogens.”

The reported studies reflect a combination of advanced computational and experimental lab work, much of which was confirmed in experiments involving mouse models and human cells. The authors acknowledged that more studies are needed to demonstrate that Tfh 10 cells can be safely managed in people, before progressing to assess the ability to boost the immune system’s response to vaccination. Nevertheless, they concluded, “Our data show that active suppression of immune responses also occurs with age and can be reversed to enhance immune responses to vaccination. These data have substantial implications for vaccination of elderly populations.”

David Hildeman, PhD [Cincinnati Children’s]

Hildeman further commented, “We are currently in the process of testing whether IL-10 blockade will restore vaccine responses in larger mammals. “If that proves effective, that would open the door to clinical trials.” Cincinnati Children’s and the co-authors have filed a patent application for their discovery. The vision – if future research is successful – is that one day seniors might receive a shot that would temporarily prevent IL-10 from interfering with the body’s response to a vaccine, but not permanently diminish IL-10 levels, and then the vaccine. “If we can achieve that, the potential impact on lives could be felt worldwide,” Hildeman stated.

The discoveries could also provide new insights that could help in the treatment of childhood diseases. “Aging starts at birth,” Hildeman noted. “Often the lessons we learn about the decline of the immune system in later years can teach us about how the immune system begins in the young. The more we learn about defective immune responses in general, and strategies to overcome them, the more we can help kids with primary immunodeficiencies, and other immunologic diseases.”

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