Friday, April 26, 2024
4/26/2024
PROJECT SUMMARY Helminth infections, which affect a billion people worldwide, especially in underprivileged counties, lead to the induction of type 2 immune response to promote clearance of the pathogens. Interestingly, this type of immune response is also induced in response to allergens and has been strongly linked to the development of allergic disorders, such as asthma. Thus, type 2 immunity can play a protective or pathogenic role. The formation of CD4+ helper type 2 (Th2) cells is a central feature of adaptive type 2 response, therefore understanding the transcriptional and metabolic mechanisms that govern the formation and function of these cells has the potential to facilitate the development of new therapeutic interventions to promote their protective functions and/or inhibit pathogenic responses with which they are associated. There is growing evidence that lipid metabolism plays a crucial role in Th2 cells, but the exact mechanisms are still poorly understood. To fill this gap in knowledge, we propose to assess the role of fatty acid transport protein 4 (FATP4), which possesses acyl-CoA synthetase (ACS) activity that promotes the activation of free fatty acids for fatty acid oxidation and complex lipid synthesis. Our preliminary data indicate that FATP4 is a novel regulator of Th2 cells as deletion of this protein in T cells resulted in an increase in the basal number of Th2 cells in the mesenteric adipose tissue and colon. Most strikingly, deletion of FATP4 in T cells or IL-5-secreting cells led to increased resistance to a helminth infection, thus establishing FATP4 as a novel regulator of Th2 cells. We hypothesize that the failure to promote fatty acid activation in FATP4-deficient Th2 cells leads to an increase of free fatty acids that can promote the activity of ligand-activated transcription factors, such as PPAR-g to restrain Th2 responses. To test our hypothesis and to fully understand the role of FATP4 in tissue-resident Th2 cells, in Aim 1, we will examine the phenotypic and functional consequences of deleting this enzyme in response to helminth infection and in a food allergy model. This approach will allow us to examine the role of this enzyme in a both protective and pathogenic setting. In Aim 2, we will utilize lipidomics and genome-wide sequencing assays to assess the changes in the intracellular lipid content, transcription, and chromatin accessibility. The interactive analysis of the collected data will allow us to define the molecular mechanism by which FATP4 regulates Th2 cells. Collectively, the result of this work will provide us with an insight into the role of fatty acid metabolism in Th2 cells and has the potential to contribute to the development of novel treatments for illnesses mediated by type 2 immunity.
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