In an autoimmune reaction, immune cells, such as T cells, attack the body's own healthy tissues by mistake. The basis for this is a breakdown of T cell immune tolerance. Among the organs that can be affected by autoimmune reactions, the skin is specifically plagued by those misguided reactions against self-tissues. The current application is designed to elucidate the mechanisms that control in vivo T cell reactions directed at a skin-restricted antigen and their role in skin autoimmunity. Specifically, the candidate will analyze two main types of T cells involved in an autoimmune response: pathologic effector T cells and protective regulatory T cells. The balance between those two types of T cells determines the outcome of an immune reaction. Research will focus on uncovering mechanisms of differentiation and maintenance of these effector and regulatory T cells in the skin. Specifically, the candidate will investigate (1) early events in the immune reaction when the T cells make initial contact with the self-antigen and define the conditions that favor the generatio of regulatory T cells and (2) late events that influence the maintenance of regulatory versus effector T cells in the skin. The candidate will utilize a novel mouse model that she has recently established. That model of skin autoimmunity allows to meticulously dissect individual mechanisms and signals that control T cell responses during the course of an autoimmune reaction. Understanding how stimulatory signals during antigen-contact impact differentiation, survival, and maintenance of regulatory T cells in tissues will provide a foundation for future work aimed at skewing the balance between regulatory and effector T cells in the skin. The long-term goal is to therapeutically interfere with the activation, generation and maintenance of regulatory T cells to treat autoimmune and chronic inflammatory skin disease.
Chronic inflammatory skin diseases such as psoriasis and eczematous dermatoses are associated with a significant amount of morbidity and markedly reduced health-related quality of life. The psychological and economic burden of these diseases on patients is profound. The research outlined in this proposal aims to enhance our understanding of inflammatory skin diseases and provide a foundation for novel therapeutic strategies.
|Gratz, Iris K; Rosenblum, Michael D; Maurano, Megan M et al. (2014) Cutting edge: Self-antigen controls the balance between effector and regulatory T cells in peripheral tissues. J Immunol 192:1351-5|