Our understanding of immunity largely stems from models of infection with pathogenic microbes. However, the vast majority of microbial-immune encounters occur as a symbiotic relationship with the commensal microbiota. Recently, the contribution of commensal-specific T cells to host physiology has received significant attention. These commensal-specific responses not only control microbiota containment but also promote antimicrobial defenses via their action on both innate and epithelial cells. Local tuning of keratinocytes by commensal-specific T cells also contributes to tissue repair following skin injury. Conversely, aberrant immunity to commensal microbes has been proposed to underlie pathologies of barrier tissues, including atopic dermatitis and inflammatory bowel disease. A better understanding of the properties and functions of commensal-specific T cell responses is therefore fundamental to studies of tissue immunity in health and disease. Our long-term goal is to better understand how commensal-specific T cell responses contribute to barrier tissue homeostasis, and the objective in this application is to investigate the mechanisms regulating cytokine production during skin injury and wound repair. Our rationale for the proposed work is that uncovering these mechanisms has the potential to translate into new therapeutic approaches. Our central hypothesis is that commensal-specific T cells are sentinels of the skin tissue and contribute to wound repair through rapid production of type-2 cytokines in response to tissue injury. In this proposal, we will focus on two mechanisms, the post-transcriptional regulation of IL-5 and IL-13 cytokine production by commensal-specific T through RNA-binding proteins and induction of the integrated stress response. Based on strong preliminary data, we will test three specific aims: (1) Understand the key proximal and distal IL-18R-signaling pathways that trigger poised type-2 immunity in commensal-specific CD8+ T cells. We have recently found that IL-18 acting directly on CD8+ T cells can trigger rapid production of IL-5 and IL-13. We will test the hypothesis that pathways unique to IL-18R, but not other IL-1R family members triggers poised type-2 immunity in commensal-specific CD8+ T cells. (2) Determine the role of Untranslated regions (UTR) of Il5 and Il13 mRNA in poised type-2 immunity in commensal-specific CD8+ T cells. We have identified multiple RNA-binding protein motifs in the UTR of Il5 and Il13 mRNA. We will test the contribution of these regulatory elements to poised type-2 immunity in commensal-specific CD8+ T cells. (3) Understand the contribution of the integrated stress response to post-transcriptional regulation of Il5 and Il13 mRNA in commensal-specific CD8+ T cells and the contribution to wound repair. Our approach is innovative as it investigates new mechanisms of immunity unique to commensal-specific T cell responses. The proposed work is significant because it will establish new insights into the interaction and communication between commensal microbes and immune cells in the skin microenvironment and identify potential targets for therapeutic intervention in conditions of chronic non-resolving wounds and skin infection.
The proposed research is relevant to the mission of the NIH because a better understanding of the mechanisms by which immune responses to commensal microbes will contribute to treatment of inflammatory, immune- mediated and autoimmune disorders. The proposed work is of particular relevance to host defense and wound repair, and to immune-mediated diseases such as atopic dermatitis.