IL-9 Represses Intestinal Granzyme A Positive CD4 T Cells in Mice with Allergic Airway Inflammation

Abstract

Abstract Mediated by immune responses in the airways, symptoms of allergic airway diseases include shortness of breath, difficulty breathing, and wheezing. Responses in distant tissues, such as increased lymphocyte proliferation and cytokine secretion, are also exhibited. How airway sensitization mediates these distant effects is unclear. We recently described the development and function of granzyme A-expressing T cells that control intestinal inflammation. Using models of chronic and memory allergic airway inflammation, we now show that a granzyme A expressing CD4 T cell population in the intestine increases during these diseases. This response is amplified in mice that lack IL-9 signaling through a deficiency in IL-9 receptor levels (IL9RKO) or receive an IL-9 antibody blockade. In a chronic intranasal allergen challenge model, we saw elevated levels of granzyme A expressing CD4 T cells in IL9RKO mice when compared to wild-type controls. In a memory internasal allergen model using wild-type mice (chronic allergen exposure, followed by an allergen-free rest period, and an allergen re-exposure), granzyme A expressing cells in the intestine were increased upon IL-9 antibody blockade. Blocking IL-9 or administering IL-9 to naïve mice or cell cultures that generate granzyme A expressing T cells did not affect cell prevalence. Therefore, concurrent allergic airway inflammation seems to be required for the proliferation of these granzyme A expressing T cells. Together, these studies suggest that allergic airway inflammation increases granzyme A expressing CD4 T cells in the intestine and that IL-9 attenuates this effect. Moreover, these results show that allergic airway inflammation impacts immunity at a distant mucosal site.