Abstract
Type 2 immunity represents a unique immune module that provides host protection against macro-parasites and noxious agents such as venoms and toxins. In contrast, maladaptive type 2 immune responses cause allergic diseases. While multiple cell types play important roles in type 2 immunity, recent studies in humans and murine models of chronic allergic diseases have shown that a distinct population of tissue-resident, CD4+ T helper type 2 (Th2) cells play a critical role in chronic allergic inflammation. The rules regulating Th2 cell differentiation have remained less well defined than other T cell subsets, but recent studies have shed new light into the specific mechanisms controlling Th2 cell biology in vivo. Here, we review our current understanding of the checkpoints regulating the development and function of tissue-resident Th2 cells with a focus on chronic allergic diseases. We discuss evidence for a barrier tissue checkpoint in initial Th2 cell priming, including the role of neuropeptides, damage-associated molecular patterns, and dendritic cell macro-clusters. Furthermore, we review the evidence for a second barrier tissue checkpoint that instructs the development of multi-cytokine producing, tissue-resident Th2 cells that orchestrate allergic inflammation. Lastly, we discuss potential approaches to therapeutically target tissue-resident Th2 cells in chronic allergic diseases.