A team of researchers at the University of Toronto has found that in utero inhibition of molecular signaling in the lymphotoxin (LT) pathway, long known as important in the development of the immune system, prevented a robust antibody response in adult mice to rotavirus, which in humans causes an estimated 215,000 deaths annually, mostly in the developing world.
That early disruption limits the ability of the immune system to later trigger and generate production of Immunoglobulin A (IgA) antibodies, the researchers showed. It also interferes with the nature and function of cells in the gut that support the antibody response, called mesenteric lymph node stromal cells.
The team published its study (“Early-life programming of mesenteric lymph node stromal cell identity by the lymphotoxin pathway regulates adult mucosal immunity”) in Science Immunology.
“Redundant mechanisms support immunoglobulin A (IgA) responses to intestinal antigens. These include multiple priming sites [mesenteric lymph nodes (MLNs), Peyer’s patches, and isolated lymphoid follicles] and various cytokines that promote class switch to IgA, even in the absence of T cells. Despite these backup mechanisms, vaccination against enteric pathogens such as rotavirus has limited success in some populations. Genetic and environmental signals experienced during early life are known to influence mucosal immunity, yet the mechanisms for how these exposures operate remain unclear. Here, we used rotavirus infection to follow antigen-specific IgA responses through time and in different gut compartments,” the investigators wrote.
“Using genetic and pharmacological approaches, we tested the role of the lymphotoxin pathway—known to support IgA responses—at different developmental stages. We found that LT-Beta receptor (LTβR) signaling in early life programs intestinal IgA responses in adulthood by affecting antibody class switch recombination to IgA and subsequent generation of IgA antibody-secreting cells within an intact MLN. In addition, early-life LTbetaR signaling dictates the phenotype and function of MLN stromal cells to support IgA responses in the adult. Collectively, our studies uncover new mechanistic insights into how early-life LTBetaR signaling affects mucosal immune responses during adulthood.”
“It was surprising that these non-immune stromal cells were so important to the immune response,” said Jennifer Gommerman, PhD, a professor of immunology at the University of Toronto, and principal investigator on the study. “It turns out that stromal cells affect the ability of immune B cells to produce IgA that neutralizes rotavirus. We’re just beginning to understand the influence these stromal cells can have.”
Gommerman said the findings highlight the growing importance of research on the environment in which immune cells function. “We typically think of a lymph node as just a bag of lymphocytes, but there is also this supporting structure that clearly has an active role in shaping immunity.”
The study’s first author, postdoctoral fellow Conglei Li, PhD, identified a broad subset of stromal cells that affect the immune response to rotavirus. But the key players are likely a subset of that subset, Gommerman said. Single-cell RNA sequencing should soon enable researchers to identify many more of those cells, she added.
That work could, in turn, lead to a better understanding of the genetic and environmental factors that may undermine immunity to rotavirus in the developing world, where rotavirus vaccines are much less effective than in high-resource settings.
Gommerman said that while several dysfunctions in the immune system likely contribute to reduced immunity to rotavirus in low-income countries, the current study offers a hint that prevention may be possible.
“The thinking would be that if you’re pregnant in a resource-depleted area, you may take a dietary supplement at a specific point to ensure proper development of tissues that support immunity, and which enable a vaccine to be more effective,” she said.
That kind of intervention is likely a long way off, said Gommerman, and replicating her results in human pregnancy presents obvious ethical problems. A more immediate next step for her lab is a collaborative study on IgA immune responses to other pathogens such as norovirus, another highly contagious disease.
A focus on single pathogens is useful in studies of IgA, noted Gommerman, because so many factors can influence IgA response. “If you simplify the system of study, you get more predictable kinetics and can ask more discrete questions,” she said. “We’ve made a contribution with that approach, on a question that has been percolating in several labs for years. That feels good.”