Resident Memory T Cells

Project Summary Resident memory T cells (Trm) are widely distributed throughout the body, remarkably abundant, and protect against local reinfections and control tumors. Unfortunately, Trm also drive many undesired immune responses including certain autoimmune, allergic, chronic inflammatory, and graft-versus-host diseases. Gaps in understanding resident memory T cell development and poor knowledge of how Trm actually function in tissues is impeding our ability to leverage or manipulate this recently defined cell type for developing new vaccines, cancer therapies, or treatments for many T cell driven diseases. This proposal will develop new mouse and human assays to define how Trm function by amplifying signals through local stromal, hematopoietic, and parenchymal cells. Systemic endocrine consequences of Trm activation will be assessed in vivo. Combinatorial gene editing approaches will expand our understanding of the molecular regulation of Trm induction. And application of a newly developed mouse model, allowing exacting manipulation of antigen responsiveness, will be used to dissect the role of antigen in shaping Trm differentiation during acute and persistent infections or cancer. Collectively, this proposal will identify new strategies for promoting or engineering Trm development, with relevance for protecting against infection or cancer, and new strategies for interfering with Trm function, with relevance for treating inflammatory diseases.