Lipid shuttling in memory Th2 cell fate and function in allergic asthma

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Project Abstract Defining how allergen-specific, memory Th2 cells develop and function has the potential to change our therapeutic approach to allergic asthma, the most common asthma subtype. Th2 cells are a dominant source of type 2 cytokines IL-4, IL-5, and IL-13, which orchestrate inflammation in murine models and humans with allergic asthma. In addition, allergen-specific, memory Th2 cells persist in vivo, driving recurrent allergic inflammation upon allergen re-exposure. We recently showed that tissue-resident memory Th2 cells (Th2 Trm) that durably persist in the lungs are a transcriptionally distinct memory Th2 cell subset that is critical for orchestrating recurrent allergic airway inflammation (Rahimi et al., Journal of Experimental Medicine, 2020). Identifying the mechanisms promoting the development and function of Th2 Trm has the potential to yield new therapeutic targets for allergic asthma. The objective of this proposal is to define the role of the transcription factor PPARg and lipid shuttling in tissue-resident memory Th2 cell development, identity, and function in a murine model of allergic asthma. PPARg is a lipid sensor and nuclear receptor family member, which orchestrates lipid metabolism. Compared to other CD4+ T helper cells, effector Th2 cells exhibit markedly higher expression of PPARg. PPARg activity during initial Th2 differentiation suppresses a Th17 cell program and is required for Th2 cell effector function. A diverse group of polyunsaturated fatty acid (PUFA) ligands, including arachidonic acid and eicosanoids, bind PPARg and promote its transcriptional activity. The central role of PPARg in Th2 cell differentiation and effector function raises important questions regarding the regulation of PPARg activity in Th2 Trm development and function: Does the degree of PPARg activity in effector Th2 cells regulate differentiation into Th2 Trm? Given that PUFA ligands are required for PPARg transcriptional activity, do Th2 Trm depend on PUFA stores that can be used to maintain and upregulate PPARg transcriptional activity during recall responses? In this proposal, we will test the hypothesis that persistent PPARg transcriptional activity promotes Th2 Trm development. We further hypothesize that storage of PUFAs in Th2 cells is required to maintain PPARg activity and promote Th2 Trm development and function. Specifically, we propose to (1) define the role of persistent PPARg activity in Th2 Trm development and identity and (2) define the role of lipid storage and shuttling in Th2 Trm development and function. We propose novel experimental approaches to test our model that persistent PPARg activity, which is maintained by intracellular stores of PUFAs, promotes Th2 Trm development and function. Defining the mechanisms whereby peripheral tissues are imprinted with allergen-specific, Th2 Trm has great potential to identify novel therapeutic targets for allergic diseases including asthma.