Scientists Identify Subset of T-Cells at the Root of Allergies

Veronica Hackethal, MD

August 03, 2017

Scientists have identified a subset of hyperresponsive immune cells that trigger allergic responses and may explain why some people develop allergies whereas others do not.

This subset of immune cells is "remarkable" because it can be easily found in laboratory analyses in every allergic individual they tested, the researchers write in an article published August 2 in Science Translational Medicine.

"The vast majority of allergen-specific T cells in allergic individuals with either food, pollen, pet's dander, mold, or house dust mite allergy fall into this subset and were preferentially deleted during allergen-specific immunotherapy," write Erik Wambre, PhD, from the Benaroya Research Institute at Virginia Mason, in Seattle, Washington, and colleagues.

The findings could pave the way for more effective allergy drugs. They could also be used to develop biomarkers for allergic disease and to help gauge how well immunotherapy is working.

Dr Wambre and colleagues have dubbed these allergen-specific immune cells TH2A cells. They are part of a group of immune cells called TH2 cells, or type 2 "helper" cells, which have long been implicated in allergy and asthma. Until now, scientists could not distinguish between TH2 cells that help the body defend against pathogens and those that are associated with the overactive immune responses typical of allergies.

Because TH2 cells as a group may display a variety of cell surface receptors, the researchers hypothesized that some subset of receptors might play a role in in allergic diseases. Identifying different cell surface markers for TH2A cells compared with classical TH2 cells would help scientists develop new biomarkers and medications that target just TH2A cells.

Therefore, the researchers screened a large panel of cell surface markers on white blood cells, including allergen-specific T cells, from both children and adults with alder tree pollen allergy. As predicted, they were able to identify a distinct signature of six cell surface markers for TH2A cells that were significantly different from classical TH2 cells (greater than 20% change, P < .001). TH2A cells overexpressed two cell surface markers (CD161 and CD49d) and down-regulated four markers (CD27, CD45RB, CCR7, and CD7).The tests also found the cell surface marker CRTH2 to be the most reliable marker for human TH2 cells as a group.

To show that these results applied to other types of allergies, researchers performed more laboratory experiments using white blood cells from 80 people with peanut, cat, dust mite, mold, or seasonal pollen allergies. White blood cells from 34 people without allergies served as controls. Results showed that regardless of the type of allergy, TH2A cells were found at high levels in people with allergies, but were largely absent from people without allergies.

Dr Wambre and colleagues next looked at 10 people with hay fever and found that TH2A cells were activated during, but not outside of, the pollen season.

They also evaluated people with peanut allergy who were part of a study testing an oral immunotherapy. Results showed that the TH2A cells were activated during allergen challenge with peanut flour, and that levels of TH2A cells decreased when participants achieved allergy desensitization through immunotherapy.

Moreover, genetic analysis showed that certain genes involved in inflammatory or allergic disease were upregulated in TH2A cells in people with allergies, but these pathways were not upregulated in classical TH2 cells or in people without allergies.

In a linked editorial, David J Cousins, PhD, from the University of Leicester in the United Kingdom, writes that the study brings researchers one step closer to understanding how T cells contribute to allergic disease, and discussed several clinical implications of the study.

"The study by Wambre et al. implicates a new pathogenic TH2 cell subset in allergic disease and reveals a panel of cell surface markers that the research community now can use to examine the importance of these pathogenic TH2 cells in clinical trials of new therapeutic agents," he wrote.

More research will be needed about mechanisms underlying how TH2A cells differentiate, what transcription factors direct the pathogenic TH2A response, and the role of specific cytokines in regulating TH2A function and activation.

The study was supported by the National Institutes of Health, Food Allergy Research and Education, Immune Tolerance Network, and Aimmune therapeutics. Dr Wambre and one coauthor are inventors on a patent/patent application held/submitted by the Benaroya Research Institute involving detection of the Th2A response. Dr Cousins reports receiving grant funding from Asthma UK, Medical Research Council, Biotechnology and Biological Sciences Research Council, GlaxoSmithKline, MedImmune, Midlands Asthma and Allergy Research Association, and the National Institute for Health Research Leicester Biomedical Research Centre.

Sci Transl Med. Published online August 2, 2017. Article full text, Editorial full text

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