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.