Asthma is a complex inflammatory disease thought to reflect a dysregulated Immune state established at the epithelial interface in the lung. Although subgroups of patients with different types of Inflammation have been described, allergic asthma, as represented by increased numbers of innate and adaptive IL-4/IL-13- expressing cells, remains highly prevalent. Despite this Insight, understanding the process(es) by which allergic asthma is Initiated will require studies in mice, where recent findings Implicate crosstalk between the lung epithelia and innate immune cells. An innate non-B, non-T, non-NK lymphocyte population present in mice and humans has gained attention through the capacity to respond to epithelial cytokines IL-25 and IL- 33 by release of large amounts of IL-13 and IL-5. Using cytokine reporter mice that accurately function-mark immune cells, we have succeeded in tracking and deleting these cells, which we designate innate helper type-2 or iH2 cells, through their capacity to generate either of these cytokines. Given the central role of IL- 13 and IL-5 In mediating tissue alterations important in asthma and allergic immunity, we propose two specific alms to study the function ofthese cells in allergic lung Inflammation.
Specific Aim 1. To establish lineage and function marking of iH2 cells In order to reveal their quantitative contributions to allergic lung immunity during physiologic challenges and to compare this with cytokine- mediated activation.
Specific Aim 2. To assess the functional requirements for IH2 cells during allergic challenges and In immune homeostasis, and to examine the physical positioning ofthese cells in lung tissues In situ. Insights from these two Specific Alms will be used to guide the choices of probes and profiles that will enable the study ofthese cells In bronchoaiveolar lavage and airway samples collected from patients with allergic asthma. (LAY SUMMARY). Asthma remains the most prevalent chronic debilitating disease of childhood and a major contributor to health care costs in the United States. These studies seek to understand the early steps required to generate an inflammatory lung response resembling asthma using model systems In mice.

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