Scientists have long believed that a newborn’s immune system was an immature version of an adult’s, but new research shows that newborns’ T cells – white blood cells that protect from disease – outperform those of adults at fighting off numerous infections.

These results help clarify why adults and infants respond differently to infections and pave the way for controlling T cells’ behavior for therapeutic applications.

This discovery was described in a paper, “The Gene Regulatory Basis of Bystander Activation in CD8+ T cells,” which published Feb. 23 in the journal Science Immunology. Brian Rudd, associate professor in the Department of Microbiology and Immunology in the College of Veterinary Medicine, and Andrew Grimson, professor in the Department of Molecular Biology and Genetics (College of Arts and Sciences), co-led the study.

“The immune system is almost always viewed from an adult perspective,” Rudd said. For example, adult T cells outperform newborn T cells at tasks including recognizing antigens, forming immunological memory and responding to repeat infections, which has led to the belief that infants’ T cells were just a weaker version of the adult ones. But during the COVID-19 pandemic, many were surprised by the apparent lack of illness in infants, bringing this long-standing belief into question.

Interested in understanding these age-related differences, Rudd and Grimson discovered that newborn T cells are not deficient. Instead, they are involved in a part of the immune system that does not require antigen recognition, the innate arm of the immune system. While adults T cells use adaptive immunity – recognizing specific germs to then fight them later ­– newborn T cells are activated by proteins associated with innate immunity, the part of the immune system that offers rapid but nonspecific protection against microbes the body has never encountered.

“Our paper demonstrates that neonatal T cells are not impaired, they are just different than adult T cells and these differences likely reflect the type of functions that are most useful to the host at distinct stages of life,” Rudd said.

Neonatal T cells can participate in the innate arm of the immune system. This enables newborn’s T cells to do something that most adult T cells cannot – respond during the very first stages of an infection and defend against a wide variety of unknown bacteria, parasites and viruses.

“We know that neonatal T cells don’t protect as well as adult T cells against repeat infections with the same pathogen. But neonatal T cells actually have an enhanced ability to protect the host against early stages of an initial infection,” Rudd said. “So, it is not possible to say adult T cells are better than neonatal T cells or neonatal T cells are better than adult T cells. They just have different functions.”

The team also found that these innate neonatal T cells persist into adulthood in both mice and humans and play unique roles during infection. The team believes that in adults, these neonatal T cells may respond to inflammation that occurs during an infection, in cancer and in autoimmune diseases.

As part of their research, Rudd and his collaborators identified the molecular mechanisms that allow T cells to respond to inflammation and switch between innate and adaptive functions.

“We now know the key epigenetic and transcriptional programs that distinguish neonatal T cells from adult T cells at the individual cell level,” Rudd said. This knowledge is essential to developing medical applications for controlling T cells’ behavior in specific ways.

The technology that is now available to study gene regulation of immune cells at the single-cell level allowed Rudd and Grimson to provide “new insight into a poorly understood biological process at a very in-depth level.”

“Being able to go from observing a unique function of T cells to a molecular mechanism is really exciting,” Rudd said. “And this was possible because we were able to combine the expertise in cellular and developmental immunology in my lab with the tools to study gene regulation in Andrew’s lab.”

Following up on his discovery, Rudd wants to study the neonatal T cells that persist into adulthood in humans. “We are also interested in studying how changes in the relative numbers of neonatal T cells in adults contributes to variation in the susceptibility to infection and outcomes to disease,” he said.

The large, multi-institution project also included collaborators at University of Rochester and University of Washington.

This work was supported by the National Institute of Allergy and Infectious Disease and the National Institute of Child Health and Human Development, in the National Institutes of Health.

Elodie Smith is a writer for the College of Veterinary Medicine.