Project Summary/Abstract Although long thought to be a unique feature of adaptive cells such as T and B cells, it is now clear that tissue structural cells can also harbor ‘memory’ of prior inflammatory responses in the form of stable epigenetic modifications that alter their transcriptional potential and behavior following subsequent tissue damage, and this is referred to as ‘inflammatory memory’. This highlights key gaps in our knowledge of T cell-tissue cross- talk that this proposal seeks to address. The premise of this proposal is that cutaneous T cells reprogram local keratinocytes and fibroblasts during inflammation, thereby altering their transcriptional and epigenetic landscape, function, and responses to subsequent stimuli, and that this influences the course and resolution of inflammatory skin disease. To fill these key knowledge gaps, we will examine the cross-talk between T cell and structural cells in innovative cell culture systems to monitor changes in cell behavior and function, and mechanistically link them to transcriptional and epigenetic reprogramming by T cell-derived cytokines. We will also leverage an established and highly manipulatable murine model of T cell-dependent skin inflammation to examine the development of inflammatory memory in KCs and Fibs in vivo, to mechanistically identify important cytokines and epigenetic mediators, and to assess the functional consequences on subsequent inflammatory and tissue-repair responses. Finally, we will analyze signatures of inflammatory memory in tissue samples from patients with the common skin inflammatory diseases psoriasis and atopic dermatitis, and assess epigenetic reprogramming in a preclinical model as a new therapeutic modality to reset inflammatory memory and break the inflammatory cycle in the skin of these patients.