Th2 Memory in Chronic Type 2 Inflammation

About This Grant

Project Summary Immune responses to cancer and chronic infection often collapse, corresponding to progression of disease. This collapse is not inevitable, however, and both natural and therapeutic exceptions have been shown occur through re-invigoration of a stem-like progenitor population of T cells. It remains unknown how aberrant type 2 responses are maintained in the face of chronic antigen exposure, rather than succumbing to immune exhaustion or tolerance. In a large scale informatic survey of human type 2 inflammation, we recently identified a stinkingly abundant progenitor-like Th2 population in human disease tissue, the Th2 multipotent progenitor (Th2-MPP). We propose that this aberrant tissue progenitor acts as the mirror image of the exhausted T cells seen in cancer and chronic infection, in this case causing pathology through overactivity of the T cell progenitor system. This project sets out to define the factors that sustain the Th2 progenitor population using human disease tissue and a novel mouse model. The experiments in this proposal are designed to reveal the core features of tissue human and mouse Th2 progenitors and to identify the factors that promote their maintenance. In Aim 1, we will deconstruct the Th2 compartment by comparing aspirin-exacerbated respiratory disease (AERD) and chronic rhinosinusitis with nasal polyposis (CRSwNP), two diseases that are clinically similar, yet thought to be driven by different factors. Using single-cell RNA-seq with T cell receptor-seq, multiomics, spatial in situ transcriptomics, single-cell metabolism assessment, and high-dimensional flow cytometry, we will identify the core and distinct features of the human Th2 compartment including the Th2-MPP population. In Aim 2, we will utilize a newly-developed chronic, multi-allergen mouse asthma model that recapitulates key features of human tissue type 2 inflammation, including a tissue Th2-MPP population that is sufficient to cause airways hyperactivity on adoptive transfer. We will utilize this new model to transcriptomically define the mouse Th2 progenitor in fine resolution and test the disease-causing capacity of this population in vivo. In Aim 3, we will use both a human in vitro system and our new mouse model to test the impact of ongoing T cell receptor signaling, TSLP, IL-33, and glucocorticoid on the Th2 progenitor population. Through these aims, our proposal will use human and mouse systems and cutting-edge approaches to define in detail a previously unrecognized human Th2 progenitor population present across type 2 disease tissues, with the potential to sustain multiple key Th2 lineages. These studies will lay the groundwork for targeting this progenitor system, with the goal of disease modification.