Scientists from the department of microbiology and immunology at the Indiana University School of Medicine and collaborators at other institutions report that they are looking at new ways to treat seasonal or intermittent asthma. Their study (“Allergic airway recall responses require IL-9 from resident memory CD4+ T cells”) appears in Science Immunology.

“Asthma has no cure and current treatments primarily focus on resolving the symptoms,” said Ben Ulrich, PhD, lead author of the study. “While spending time in the high-risk asthma clinic at Riley Hospital for Children, I observed many patients had a more intermittent disease course. We went into the lab and developed models to more accurately define allergic memory and recall response in the lung.”

When someone with seasonal or intermittent asthma breathes in allergens, they can have symptoms such as wheezing, coughing and, in severe cases, asthmatic exacerbation or hospitalization. These symptoms result from inflammation, airway constriction, and mucus production. Once exposed to the seasonal allergens, which include exposure to pollens, fungi or other allergens only prevalent at certain times of the year, antigen-presenting cells activate CD4 positive T-cells to secrete cytokines, starting inflammatory cascades.

The team focused one cytokine, interleukin 9 (IL-9), to see how it impacts allergic memory responses. They found a unique population of memory CD4 T-cells that produced IL-9, along with IL-5 and IL-13. These cells secreted IL-9 in an antigen-specific manner. Additionally, these cells express ST2, which is an IL-33 receptor, and demonstrated amplified IL-9 production in the presence of IL-33 in an allergen-specific manner.

Blockade of IL-9 led to a decrease in expression of several genes associated with mucus production in the epithelial cells. It also led to a decrease in CD4 T-cells and B-cells and altered expression of activation markers on microphages.

“Asthma is a chronic inflammatory lung disease with intermittent flares predominately mediated through memory T cells. Yet, the identity of long-term memory cells that mediate allergic recall responses is not well defined. In this report, using a mouse model of chronic allergen exposure followed by an allergen-free rest period, we characterized a subpopulation of CD4+ T cells that secreted IL-9 as an obligate effector cytokine,” write the investigators.

“IL-9–secreting cells had a resident memory T cell phenotype and blocking IL-9 during a recall challenge or deleting IL-9 from T cells significantly diminished airway inflammation and airway hyperreactivity. T cells secreted IL-9 in an allergen recall–specific manner, and secretion was amplified by IL-33. Using scRNA-seq and scATAC-seq, we defined the cellular identity of a distinct population of T cells with a proallergic cytokine pattern.

“Thus, in a recall model of allergic airway inflammation, IL-9 secretion from a multicytokine-producing CD4+ T cell population was required for an allergen recall response.”

“Asthma exists in multiple forms and seasonal or intermittent asthma can be very different from other forms because of chronic exposure to allergens,” said Mark Kaplan, PhD, chair of the department of microbiology and immunology at the IU School of Medicine. “This study demonstrates targeting IL-9 in the lungs during seasonal allergies could help with lung inflammation. By focusing on a population of memory cells that mediate the allergic recall responses of the lungs, we could develop new targets for treatments.”

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