Scientists have long believed that a newborn’s immune system was an immature version of an adult’s, but research from Cornell University shows that newborns’ T cells—white blood cells that protect from disease—outperform those of adults at fighting off numerous infections. The new study describes why these T cells behave in a way that is more similar to innate immune cells—and fight pathogens before immune memory exists—rather than responding like normal adaptive immune cells.

The work, involving experiments with mice and with observations corroborated by fetal, neonatal, and adult human data, also suggests that chromatin remodeling is a crucial step for innate-like T cell function. The results help clarify why adults and infants respond differently to infections and could point to strategies for controlling T cell behavior that have therapeutic applications.

Research co-leads Brian Rudd, PhD, associate professor of microbiology and immunology, and Andrew Grimson, PhD, professor of molecular biology and genetics, and colleagues reported on their findings in Science Immunology, in a paper titled “The gene regulatory basis of bystander activation in CD8+ T cells.” In their paper, the team concluded, “Thus, CD8+ T cells are capable of protecting the host against infection via the canonical antigen-dependent (adaptive) response and also via the poorly understood antigen-independent (innate) response.”

CD8+ T cells play an essential role in protecting against intracellular pathogens, the authors explained. The cells, activated via their T cell receptors (TCRs) when presented with microbial peptides, expand and differentiate into subsets of effector and memory cells. “On the basis of their ability to respond to specific foreign antigens and form immunological memory, CD8+ T cells are part of the adaptive immune system,” the team continued.

There are  differences between T cells in adults, and in newborns. For example, adult T cells outperform newborn T cells at tasks including recognizing antigens, forming immunological memory and responding to repeat infections, and this has led to the belief that infant’s T cells may be a weaker version of adult T cells.

However, during the COVID-19 pandemic scientists were surprised by the apparent lack of illness in infants, bringing this long-standing belief into question. And, as the authors wrote in their paper, a subset of naive, antigen-inexperienced CD8+ T cells can be activated during early stages of infection in an inflammation-dependent but TCR-independent “bystander” manner.

Rudd and Grimson carried out a multiomics study to define how neonatal CD8+ T cells in mice establish their innate-like functions. Their analyses involving chromatin accessibility profiling and single cell transcriptomics characterized how the cells act as bystanders, ready to act by tuning the activity of the transcription factors Bach2 and AP-1. “… we used high-dimensional flow cytometry, RNA sequencing (RNAseq), assay for transposase-accessible chromatin using sequencing (ATAC-seq), and single-cell profiling to identify the key epigenetic programs and transcription factors (TFs) that allow neonatal CD8+ T cells to be more responsive to inflammation,” they explained. They found that, as the cells respond, their chromatin rapidly remodels to support innate anti-pathogen activity.

Their results indicated that newborn T cells are not deficient, rather, they are involved in the innate arm of the immune system that does not require antigen recognition. “Previous studies have suggested that CD8+ T cells produced in early life have more innate-like functions, whereas those generated in adulthood have more adaptive functions,” they pointed out.

So, 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.

Perhaps one of the most “unexpected findings” from the study, the team noted, is that neonatal CD8+ T cells are more responsive to inflammation than adults because of their ability to undergo chromatin remodeling. “Using a multi-omics approach, we found that the ability of neonatal CD8+ T cells to respond to innate cytokines derives from their capacity to undergo rapid chromatin remodeling, resulting in the usage of a distinct set of enhancers and transcription factors typically found in innate-like T cells,” they stated.

The ability of neonatal T cells to participate in the innate arm of the immune system enables these cells in newborns 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,” Rud said. “But neonatal T cells actually have an enhanced ability to protect the host against early stages of an initial infection. 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 detected the continued persistence of innate-like T cells in adult mice and adult humans, although in smaller numbers for the latter. Following up on the discoveries, 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.

In their paper, the authors considered why the immune system requires a more functionally diverse CD8+ pool of neonatal T cells. They suggested that in early life, the neonatal immune system must protect the host against “a large swath of pathogens,” but with only a constrained set of T cells that lacks immunological memory. “Thus, it is likely beneficial for the neonatal T cell pool to be highly responsive to inflammation and quickly generate a variety of cytokines and effector molecules, in hopes that the cost of making some unnecessary cytokines is outweighed by the benefit of making a variety of cytokines that could potentially be useful against diverse pathogens,” they wrote.

The authors say more research will be needed to answer questions relating to the impact of, for example, environmental factors and host genetics, on innate functions of CD8+ T cells, and to better understand the chromatin remodeling in these cells. Moreover, they pointed out, “it will be important to determine how neonatal CD8+ T cells interact with other types of immune cells to provide innate defense. Such studies will broaden our fundamental understanding of immune development and the mechanisms that regulate innate and adaptive functions.”

Previous articlePrime Editing for Isogenic iPSCs, PRINT, Universal In Vivo CAR T Editing, Biogen Q4 Results Disappoint; Andrea Choe
Next articleNovel Autoimmune Disease Trigger Uncovered