Asthma and allergies affect an estimated 235 million people worldwide and represent an important challenge for basic science to benefit clinical medicine. Our current understanding of these diseases demonstrates that Th2 cells play a major role in the type 2 inflammatory response characteristic of these diseases. However, the factors that induce T cells to differentiate towards a Th2 phenotype, and not a Th17 phenotype, remain one of the important unresolved problems in these diseases. Dendritic cells (DCs) are antigen-presenting cells central to the induction of Th2 differentiation. However the molecular mechanisms by which Th2-skewing DCs develop has remained controversial. Through studies by our group and others, the transcription factor IRF4 has emerged as a key regulator of DCTh2 development. We found that allergens that signal through FcR?-associated receptors to induce bone marrow-derived DCs (BMDC) to upregulate IRF4, and that IRF4 expression is necessary for the BMDCs production of the cytokines IL-33 and IL-10. Further, HDM-induced type 2 inflammation and Th2 re- sponses are reduced in mice lacking expression of IRF4 in CD11c+ DCs. Together, these data identify a mech- anism whereby Th2 stimuli signal through FcR?-associated receptors on DCs to induce IRF4 expression and IL- 33 and IL-10 production. The overall hypothesis of this project is that through the upregulation of IRF4 and its downstream mediators, DCs induce the development of type 2 inflammation and tissue resident memory (TRM) Th2 cells in the lungs of asthmatics and mice with experimental asthma. Understanding the mechanisms by which DCs promote asthma-type inflammation is key to the development of new targets for therapeutics. IRF4, or its downstream effector molecules, are attractive candidates for this purpose since IRF4+ DCs have been implicated in both Th2 and Th17 asthma phenotypes. Through the proposed translational study, we seek to reveal how these IRF4+ DCs function to promote type 2 inflammation in mouse models of experimental asthma and in human asthma. This research supplement application is to promote diversity in health-related research through compensation of Maile Hollinger for training and working with us toward achieving the overall goals of the parent R01 grant. Mx. Hollinger will be mentored by Dr. Sperling whose expertise is in asthma immunology, and who has suc- cessfully mentored numerous trainees. Mx. Hollinger?s project will be to study the Farm Effect by modeling it in mice and determine how dendritic cells mediate this effect. This supplement is essential for the development of this outstanding young researcher and will provide the necessary funding for completion of their PhD research in the Sperling laboratory.
PROGRAM NARRATIVE The dramatic increase in both the prevalence and severity of asthma in the United States over the past 50 years has led to increased research on the pathogenesis of the disease. Yet fundamental questions still remain. The goal of these studies is to investigate the regulation of the asthmatic inflammatory response to elucidate novel targets for therapeutic intervention.
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