The immune system must defend the host at the most likely sites of pathogen encounter--the epithelial cell boundaries between barrier organs and the host's environment. Exciting recent data demonstrate that a population of memory T cells (TRM) resides long-term within peripheral tissues and provides a first line of host defense from pathogens that cause local infection. However, in some settings, the local persistence of memory T cells that provide robust response is detrimental. TRM are thought to play a key role in local, recurring inflammatory skin diseases. This proposal seeks to address significant gaps in our understanding of the mechanisms that regulate cutaneous TRM in health and disease. Defining mechanisms that control TRM precursor localization and persistence within skin will be important for optimizing vaccines to provide local protection as well as therapies to prevent unwanted inflammation. Mechanisms that direct the interstitial migration, persistence and response of cutaneous TRM will be defined in a normal immune response to HSV infection and in autoimmune vitiligo. While the local cytokine microenvironment is known to direct TRM formation, factors that inhibit TRM differentiation/persistence are unknown. This proposal will investigate the hypothesis that depending on the cytokine microenvironment TRM formation is either promoted or inhibited. Lastly, although TRM have been identified at sites of cutaneous inflammatory disease, targeting TRM is an untested therapeutic approach. We will use a mouse model of vitiligo with clinical application to investigate the novel hypothesis that autoreactive TRM maintain depigmentation, and that depletion of autoreactive TRM will prevent and/or ameliorate disease. Up-regulating pathways that promote the persistence of T cells in peripheral tissues is a critical focus of current vaccine design; it may be equally important to create approaches that reverse these pathways to prevent unwanted TRM accumulation within inflamed tissues.
Immune cells provide protection from infectious agents, but can also cause inappropriate inflammation in autoimmune and allergic diseases. Our goal is to define the mechanisms that regulate the persistence and response of immune cells in peripheral tissues. Based on these studies, novel therapies may be developed that target immune cell accumulation within tissues, promoting the inhibition of autoimmune responses or the augmentation of immune responses to infections or vaccines.
