In one rural New York community, allergies are almost unheard of. That anomaly led researchers to examine how the local environment might shape the developing immune systems of infants.

The findings could help reshape the way clinicians diagnose and treat allergies. As researchers uncover new T-cell subsets and environmental influences on T-cell activity, allergies could be identified by simple blood tests, and probiotic combinations could provide long-term protection against allergies.

“Most of the studies had looked at older children and adults and I felt very strongly — knowing that allergies start in early life — the first year of life is key,” said Kirsi Jarvinen-Seppo, MD, PhD, chief of pediatric allergy and immunology at the University of Rochester Medical Center, Rochester, New York.

Her instincts proved correct. She observed differences between the T cells of the rural infants and infants from Rochester and its suburbs, starting when babies were just 6 months old. The findings built on growing research that began in 1995, when Shimon Sakaguchi, MD, PhD, a professor of immunology at the University of Osaka, Suita, Japan, discovered regulatory T cells (Tregs) and their association with allergies, pointing to a gateway to potential new treatments.

Sakaguchi and two other scientists behind the Tregs discoveries won this year’s Nobel Prize in Physiology or Medicine. Their work led scientists to understand how Tregs police the allergy-triggering activity of T helper (Th) cells. For example, patients with an allergy to cow’s milk who outgrew the reaction were found to have more allergen-specific Tregs.

Immune Signals

Jarvinen-Seppo’s research raises new questions about how environmental conditions influence Tregs and Th cells. The group has recruited about 160 mothers in their second or last trimester of pregnancy, with about half from the farming community and half from more urban homes. Her team tested infants’ blood and skin at regular intervals between 2 weeks old and 2 years old. The study is ongoing and some of those infants are now 6 years old.

An effective immune response relies on a balance of Th cells and Tregs, which regulate other T cells, Jarvinen-Seppo said. Th1 cells protect against viral and bacterial infections, while Th2 cells tell B cells to release allergy-triggering antibodies called immunoglobulin E (IgE). An allergic reaction occurs when Th2 cells mistake a harmless substance as dangerous, kickstarting the production of IgE in the B cells.

“Before the discovery of Tregs, immune responses were considered either Th1 or Th2, and tolerance was a passive process,” said Magali Noval Rivas, PhD, associate director of the Infectious and Immunological Diseases Research Center at Cedars-Sinai Medical Center in Los Angeles. “We know today that Tregs regulate these Th2 responses.” 

Jarvinen-Seppo and her colleagues found elevated Tregs among infants born in the farming community and among those from Rochester who were not prone to allergies. They also identified a unique population of Th2 cells that produce highly inflammatory cytokines, promoting B cells to churn out IgE antibodies. The new subset, dubbed Th2 B cells, were associated with allergy development and more prominent in urban and suburban Rochester infants, increasing in number throughout the first year of life, she said.

Jarvinen-Seppo is now recruiting a second cohort of families and hopes to double the size of the study. She plans on testing for inflammation and skin barrier function, which are related to food allergies and eczema. Both conditions are rare among Old Order Mennonite children.

“This is a huge effort,” said Hirohito Kita, MD, of the Mayo Clinic Allergic Diseases Laboratory in Scottsdale, Arizona, who is not involved in the research. “It’s surprising, even at 6 months of age they started to see differences in the Th2 cells and regulatory T cells, indicating the importance of the environment. And I think we have to start thinking about how to change it.” 

Harnessing T cells for Allergy Treatment and Diagnosis

Genes can increase the likelihood for developing allergies, but evidence suggests the environment — particularly diet and exposure to microbes — may also play a role in the process. For instance, less microbial contact in early childhood can thwart Th1 activation, in turn boosting Th2 activity.

The environment also increases the effect of Tregs, “but it’s still not clear why,” said Beatriz León Ruiz, PhD, a senior investigator at the Laboratory of Allergic Diseases at the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland.

Jarvinen-Seppo said she suspects the gut microbiome is contributing to differences between infants’ T cells and their sensitivity to allergy.

She and her colleagues have compared the gut microbiomes of infants in the same cohort of the original study and found “striking differences,” that could affect their risk of developing allergies.

For instance, infants born in the farm setting had higher levels of bifidobacteria, which some research has shown may enhance immune development. These infants are members of an Old Order Mennonite community, where home births and large families are common. Cars that emit exhaust, pasteurized milk, and antibiotics are avoided — lifestyle differences that may affect their microbiomes, Jarvinen-Seppo said.

If more studies make this association, new allergy treatments could be developed using probiotics, she said. A clinical trial of 238 infants in the US and Australia reported preliminary results in October suggesting that giving infants a combination of probiotics significantly reduces the risk of developing skin and food allergies.

“This was big because we haven’t had probiotic combinations or therapeutics thus far that have proven efficacy,” Jarvinen-Seppo said. “I think it further illuminates that the manipulation of gut microbiome has a lot of potential.” 

Potential for prevention of allergies also abounds as scientists draw connections between infants’ microbiomes and T cell activity, León Ruiz said.

“If we understand why this is happening, we can change our habits. We can sense [whether] food or environmental exposure can modulate our immune system in a good way,” she said.

For example, a birth cohort study of 856 children living on farms or in rural areas of Europe found those fed a more diverse diet — including allergenic foods like cow’s milk and peanuts — in the first year of life were at a lower risk of developing allergies and more active Tregs than those whose diet was more limited.

The ability of clinicians to diagnose allergies could also be improved as understanding of T cell behavior expands. Take milk allergy, for example. The most reliable diagnostic method currently involves giving patients increasing doses of milk under supervision and waiting for symptoms to arise, said Bjoern Peters, PhD, a professor of bioinformatics at La Jolla Institute for Immunology in San Diego. But a blood test for T cell phenotypes could eventually be used instead.

Peters and his colleagues have identified differences in T cell phenotypes in children with cow’s milk allergies, including increased numbers of abnormal Tregs. They applied their findings in a separate study with Johns Hopkins University this year, using T cell phenotypes to track milk tolerance among allergic children undergoing oral immunotherapy.

Eventually, a patient’s Tregs could help generate a picture of a patient’s likelihood to develop milk allergy — a simple blood test that he called a “dream application.”

Jarvinen-Seppo reported being a consultant for Biostime Institute for Nutrition and Care and has received royalties from Elsevier and grant funding from DBV Technologies and Siolta Therapeutics and the National Institute of Allergy and Infectious Diseases.

Sarah Amandolare is a freelance journalist living in New York City.