Itk Signaling and Type 1 Regulatory T Cell Differentiation and Function in Allergic Airway Inflammation
Principal Investigator: Avery August
DESCRIPTION (provided by applicant):
Lung inflammatory diseases such as allergic asthma affects almost 300 million people worldwide, with up to 11% of the population of the United States alone and its rate continues to increase in urbanized countries. This disease cannot be cured, making it one of the most expensive diseases for healthcare systems in developed countries. This makes this work highly significant. Allergic asthma is characterized by a balance of inflammatory cytokines such as those produced by Th2 and Th17 cells, and counter regulation of these cells Foxp3+ T regulatory cells (Treg) and IL10+ Type 1 regulatory T cells. While much is known about Tregs, very little is know about the intracellular signals that regulate Tr1 cell development and function. Being able to manipulate the suppression mediated by Tr1 cells is a potentially promising immunotherapeutic strategy for controlling and suppressing such lung inflammation. We have found that tyrosine kinase Itk regulates the development of Tr1 cells. Based on our results, we have developed the hypothesis that Itk regulates the development and function of Tr1 cells during lung inflammation. We propose experiments in two specific aims that will determine the role of Itk in the development and function of Tr1 cells in mice and human, and mechanism by which it does so. This work is extremely innovative as we utilize novel and unique transgenic mice and approaches, and have exciting preliminary data that when fleshed out, will provide information on a signaling pathway that could be used to manipulate the development and function of Tr1 cells during lung inflammation as well as other inflammatory conditions.