Flu Fighters: How the Immune System Protect Infants from Influenza

Investigators discover how guardian T cells help combat flu in infants and young children.

By Mike O’Kelly; Photos by Ann-Margaret Hedges and Seth Dixon

Liz Carter holds her daughter, Morgan

Risky business

Liz Carter vividly remembers the flu experience of her daughter, Morgan. Now a toddler, Morgan fought flu when she was only 5 months old. The 2018–2019 flu season already has the highest number of flu-related deaths in children since national reporting began.

It may start with a runny nose that leads to a cough. Then a fever and the aches slowly settle in — a multitude of unwelcome symptoms that by themselves are enough to raise concern in the parents of an infant. When Liz Carter’s 5-month-old daughter, Morgan, developed these symptoms in 2016, Liz suspected Morgan had the flu.

A visit to the pediatrician confirmed her suspicions. The doctor prescribed Tamiflu, and the combination of early administration of the medicine and rest helped Morgan recover quickly in a few days.

“I kept her at home and just kept her warm, trying to comfort her until she got well,” Liz says.

Because Morgan was not yet 6 months old — when most babies are able to receive their first flu vaccination — she was especially vulnerable to flu. Liz was also concerned because Morgan has sickle cell disease, for which she receives treatment at St. Jude Children’s Research Hospital.

Kids with sickle cell disease and other disorders have an elevated risk for flu-associated death.

Morgan was fortunate. Each year, hundreds of U.S. children die of influenza. According to the Centers for Disease Control and Prevention, the 2018–2019 flu season already has the highest number of flu-related deaths in children since national reporting began.

Paul Thomas, PhD, of St. Jude Immunology, and his colleagues are working to better understand how the immune system helps infants battle this dangerous disease. The findings may help clinicians save more lives.

Developing systems

Flu is dangerous for people of all ages, but it is more often lethal in infants than in older children and healthy adults because infants have smaller lungs and weaker immune systems. Thomas’ laboratory studied a group of unconventional T cells as part of a collaboration with the St. Jude Department of Bone Marrow Transplantation and Cellular Therapy. The scientists found that patients who had stem cell transplants recovered these unconventional T cells faster and with higher magnitude than did other patients.

“When we looked at other types of cells, we didn’t find any other cell type that predicted a good outcome,” Thomas says. “That got us thinking that these cells play an important role in the developing immune system.”

Because the immune systems of transplant patients develop much like those in infants, the researchers sought to further examine the effects of the unconventional T cells on the infant immune system.

Previous research had shown that gamma-delta T cells were more likely to cause inflammation than to promote tissue repair, but this recent study revealed something unexpected.

 

An unusual finding

T cells are responsible for helping the immune system form and for regulating responses to viruses and other illnesses. The unconventional T cells are named according to the protein chains that form their surface receptors. The T cells Thomas and his colleagues examined are known as gamma-delta T cells. Unlike conventional T cells, gamma-delta T cells develop before birth. These cells are found in the blood, lungs, gut and skin.

“Since gamma-delta T cells are the first immune cells we develop, we thought they might be special,” said Xi-zhi Guo, a graduate student in Thomas’ laboratory. “Their role may be to help right after birth while conventional T cells are still developing.”

Previous research had shown that gamma-delta T cells were more likely to cause inflammation than to promote tissue repair, but this recent study revealed something unexpected.

The researchers already knew gamma-delta T cells in flu-infected models produced high levels of a signaling protein called interleukin-17A. Thomas and his colleagues learned an increased amount of that protein triggered a surge in another signaling protein known as interleukin-33 in cells lining the lungs. Interleukin-33 then goes to work, recruiting other immune cells to produce a growth factor called amphiregulin, which promotes lung repair.

Nasal wash samples from infants infected with flu showed a similar connection between increased interleukin-17A and better patient outcomes.

Xi-zhi Guo and Paul Thomas, PhD

Laboratory discoveries to save lives

Graduate student Xi-zhi Guo (at left), Paul Thomas, PhD, and their colleagues discovered how the immune system strives to protect the lungs of the youngest flu patients. The findings may help clinicians save more lives.

Beyond influenza

The findings suggest that the immune systems of infants and adults take different approaches to restoring lung function. Thomas and his team would like to better understand the makeup of the immune response in infants and determine which interventions might lead to better results in the future.

“Relying on gamma-delta T cells and the amphiregulin pathway to help restore lung function could have broad-based therapeutic benefits — not just for flu, but for other viruses such as respiratory syncytial virus, adenovirus or hand-foot-and-mouth disease,” Thomas says.

From Promise, Winter, 2019

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