These microscopic critters are hard to avoid, which means nearly everyone has been exposed. [La Jolla Institute for Immunology]

The results of studies by scientists at La Jolla Institute for Immunology (LJI) may help to explain why some people suffer allergic reactions to house dust mites, but other people don’t. The research uncovered a previously unknown subset of T cells that may control allergic immune reactions and asthma from developing in response to house dust mites, and potentially to other allergens.

“We discovered new immune cell subsets and new therapeutic opportunities,” said Grégory Seumois, PhD, instructor and director of LJI’s Sequencing Core. “This new population of cells could be one, out of many unknown mechanisms, that explains why healthy people don’t develop inflammation when they breathe in allergens.” Seumois is co-lead author of the team’s published paper in Science Immunology, which is titled, “Single-cell transcriptomic analysis of allergen-specific T cells in allergy and asthma.”

House dust mites (HDM) are found in every corner of the home. Do some cleaning, and you’ll probably stir some up. But while everyone has immune cells that are capable of reacting to common allergens like house dust mites, most of us have no allergic symptoms. In contrast, other people may display allergic reactions to house dust mites that typically include sneezing, a runny nose, and itchy, swollen nasal passages. For some, the reaction may be even more severe, and trigger a potentially life-threatening asthma attack.

To treat the root cause of allergies and asthma, researchers need to know exactly what sets sufferers apart from individuals who don’t have asthma or allergies. Subsets of T cells are key to allergic responses, the authors explained. “CD4+ T helper (TH) cells and regulatory T (Treg) cells that respond to common allergens play an important role in driving and dampening airway inflammation in patients with asthma.”

House dust mites are a useful allergen to study, as these microscopic creatures are hard to avoid, which means that nearly everyone has been exposed. “HDM is one of the most common and ubiquitous allergens, and sensitization is associated with both the onset of allergic asthma and its severity,” the investigators commented. Even in people without HDM allergy, the immune system is likely to react in some way as it learns to recognize HDM molecules. This makes HDM a useful model for studying what causes allergies and asthma attacks.

The new study builds on expertise in the lab of senior study author Pandurangan Vijayanand, MD, PhD, linking gene expression to disease development. The investigators also took advantage of the Immune Epitope Database, an LJI-led resource that holds information on how the immune system interacts with allergens like house dust mites.

To investigate the immune system response that underpins HDM allergy, the LJI investigation applied single-cell RNA-seq (or single cell transcriptomics) to see exactly which genes are expressed and molecules produced by these specific T cells in response to HDM allergens. They tested cells from four groups of people, including those with asthma and HDM allergy, people with asthma but no HDM allergy, individuals with only HDM allergy, and healthy subjects.

Their analyses suggested that a subset of helper T cells called interleukin (IL)-9 Th2 expressing HDM-reactive cells is more prevalent in the blood of people with HDM-allergic asthma, when compared with those who are only allergic to HDM. Further investigation suggested that those IL9-TH2 cells increased expression of genes that increased the cytotoxic potential of those cells. “We were surprised to find that expression of several transcripts encoding products linked to pathogenicity and survival of TH2 cells was increased in IL9-expressing cells,” they wrote. “Overall, these findings suggest that IL9-expressing HDM-reactive TH2 cells displayed greater pathogenic properties that could play an important role in driving asthma pathogenesis.” Effectively, those specific T cells could kill other cells and drive inflammation.

In contrast, another subset of T cells stood out in the non-allergic subjects. These T cells expressed an interferon response signature and were enriched for a gene that encodes a protein called TRAIL. The results of the researchers’ analyses suggested that TRAIL could be important because it could diminish the activation of helper T cells. “… we hypothesize that these TRAIL-expressing HDM-reactive T cells could play an important role in dampening TH2 inflammation in allergy and asthma,” they noted.

The findings may mean that people with this specific cell population could have less T-cell driven inflammation in response to HDM allergens. And the results could provide a clue as to why some people develop allergies and asthma while others do not. “In summary, our single-cell transcriptomic study of HDM allergen–specific T cells has identified TH subsets that may contribute to the pathogenesis of allergy and asthma,” the researchers concluded. “These findings suggest that the THIFNR and TregIFNR subsets may dampen allergic responses, which may help explain why only some people develop TH2 responses to nearly ubiquitous allergens.”

“Now if functional studies confirm this dampening effect, we’re curious if there is a way to boost the activation of these T cells or induce their proliferation in asthmatic or allergic populations,” said Seumois. “Can we act on those cells very early on, before asthma has developed?”

“The study highlights the power of unbiased single-cell genomics approaches to uncover novel biology,” said Vijayanand. For example, genomics studies like this one may someday help identify children at risk of developing asthma and allergies. Early detection could open the door to preemptively acting on immune cells before development of allergy and asthma.

While Seumois emphasized that there is much more work to be done, he added that the transcriptomic method used for this study could accelerate future asthma and allergy research. “This is the first large-scale, single-cell, RNA-seq transcriptomic analysis for LJI,” said Seumois. “Now that we have developed the bench know-how and analysis pipeline, it could be applied to many diseases.”

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