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.