Despite a clear link between intestinal immunity and the microbiota, the mechanisms regulating host immune responses to commensal microbes remain poorly understood. Intestinal epithelial cells (IECs) reside at the direct interface between the microbiota and dynamic immune cells and are thus uniquely poised to calibrate host immunity. Although IECs are likely critical for deciphering harmful versus harmless antigens and instructing the appropriate immune reaction, remarkably little is known about mechanisms that enable IECs to modulate host- microbiota interactions. Antigen presenting cells (APCs) must differentiate between harmless and harmful antigens and coordinate proper T cell responses. Although atypical APCs, my preliminary data demonstrate that IECs are the most abundant MHCII-expressing cells in the intestine and that MHCII expression in IECs is directly upregulated by microbiota. Thus, I hypothesize that epithelial antigen presentation may be essential for mediating host-microbiota interactions that impact intestinal homeostasis and inflammation. Studies outlined in this proposal will directly test this hypothesis by defining the function of IEC-intrinsic MHCII. Employing newly developed mutant mouse strains, intestinal organoids, and established models of intestinal inflammation, two specific aims are proposed that will determine (i) the influence of IEC-intrinsic MHCII expression on mucosal barrier function and immune homeostasis and (ii) how IEC-intrinsic MHCII regulates development of intestinal inflammation. Collectively, these studies will provide new insights into how microbiota direct intestinal immunity and will guide novel approaches for investigating and treating intestinal inflammatory diseases. During my past research experiences, I discovered my strong interest in the host-microbiota relationship. For this reason, I initiated the proposed project with Dr. Theresa Alenghat that will build upon my knowledge of innate immunity and antigen presentation and enable me to transition into the field of mucosal immunology. My thesis work provided me with an excellent foundation in host-pathogen interactions, microbiology, and immunology, but I have not had previous exposure to epithelial regulation, antigen-specific techniques, and intestinal disease models. The labs of my mentors, Dr. Alenghat and Dr. Sing Sing Way, along with the exceptional scientific and intellectual environment at Cincinnati Children?s Hospital will enable me to utilize modern, innovative approaches in my research and collaborate with top investigators. Over the next three years, I fully anticipate that my background in conjunction with my current training plan will allow me to successfully carry out the proposed project. The mentoring and training I will receive will enable me to successfully transition to an independent research career that can address questions directed towards fundamental advances in mucosal immunity, as well as innovative and targeted strategies for investigating microbiota-sensitive diseases.

Public Health Relevance

Numerous chronic human diseases are linked to dysregulation of the symbiotic relationship between the mammalian host and commensal bacteria. The goals of this proposal are to decipher how epithelial cell antigen presentation enables commensal microbes to instruct immunity in the intestine. Understanding these mechanisms will direct new approaches for limiting or preventing commensal bacteria-influenced diseases.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1)
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Gondre-Lewis, Timothy A
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Cincinnati Children's Hospital Medical Center
United States
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