Defining the T cell state that sustains chronic allergic disease

About This Grant

Project Summary Allergic diseases persist throughout a person’s lifetime, and the mechanisms underlying maintenance of the Th2 cells that drive these diseases are poorly understood. Chronic inflammation canonically drives T cell exhaustion in chronic infection and cancer, while Th2 cells conversely persist despite chronic inflammation We recently created a single-cell transcriptomic atlas from human tissues with allergic type 2 inflammation. A conserved set of Th2 cells was identified across tissues, including an aberrant memory-like population co-expressing TCF1 and LEF1, with evidence of chronic activation. This transcriptional profile mirrors the progenitor/stem-like CD8+ T cells that have been described in cancer and chronic infection, and we hypothesized that this Th2 cell population may serve as the reservoir that perpetuates Th2 responses. We named this cell the Th2 cell multipotent progenitor (Th2-MPP). Ex vivo functional studies established that these cells couple self-renewal with terminal differentiation in Th2, TFH- like, and Treg cells. We propose that aberrant cell-cell interactions and alarmin signaling networks in allergic tissues orchestrate an epigenetic state in Th2-MPP that enables self- renewal in the face of chronic antigen burden. The specific aims of this research strategy will investigate the epigenetic mechanisms and cell- cell interactions driving human Th2-MPP maintenance (Aim 1). Moreover, we will functionally interrogate candidate pathways through the development and characterization of a mouse model of chronic type 2 pulmonary inflammation, with temporal conditional genetic ablation of putative regulators of Th2 maintenance (Aim 2). These complimentary human and mouse immunology approaches will yield fundamental insights into the chromatin states of type 2 lymphocytes in barrier tissues and signaling mechanisms that drive this profile. Concurrently, the mechanistic studies of candidate pathways in mice will establish new avenues for the development of therapeutic modalities. This study combines mechanistic mouse models and primary human tissue analyses with cutting-edge single cell bioinformatics to provide the candidate new training in key elements of translational immunology. Through support from the co-mentors and Advisory Committee, the candidate will be well-positioned to transition to independence as an investigator, with the goal of identifying new therapeutic targets for the treatment of chronic inflammatory diseases.