R01AI158687

Determinants of Induced Treg and Inflammatory Th17 Cell Balance in Response to Potentially Pathogenic Microbiota - Interactions of the Gut Microbiota with Cells of the Immune System Govern Multiple Physiological Functions that are Manifested Locally, in the Regulation of Intestinal Barrier Functions, and Systemically, in Autoimmune Diseases and Modulation of Anti-Tumor Immunity.

Although mutualistic microbial species generally provide vital health benefits to the host, some of them can conditionally cause harm under some circumstances, such as host genetic vulnerabilities or following environmental perturbation. These bacterial species, known as "pathobionts", have been proposed to be major contributors to inflammatory bowel diseases (IBD) such as ulcerative colitis and Crohn's disease, which are characterized by intestinal dysbiosis. A better characterization of these bacterial species and the mechanisms by which they interact with the host in healthy homeostatic conditions and during IBD-associated inflammation is critical for developing better therapeutic approaches.

We study the model pathobiont Helicobacter hepaticus, which induces regulatory T cells (iTreg) in the healthy murine gut, but promotes Th17-mediated inflammation when the iTregs are compromised. H. hepaticus-specific naive T cells are activated by antigen-presenting cells (APCs) in colon-draining mesenteric lymph nodes (MLN), and up-regulate FOXP3 and RORγt, transcription factors characteristic of intestinal iTreg. However, when IL-10 is limiting or when iTreg induction is otherwise compromised, the microbe-specific T cells express RORγt and adopt a pathogenic (p)Th17 cell program in the lamina propria.

The goals of this proposal are to identify the APCs that interact with naive H. hepaticus-specific T cells in the MLN to program either iTreg or pTh17 differentiation pathways, elucidate the molecules involved and the temporal dynamics of the APC-T cell interactions, and determine the roles of the diverse types of MHC class II-expressing cells in the intestinal lamina propria in promoting iTreg and pTh17 cell functions.

In preliminary studies, we found that selective loss of either CCR7 in dendritic cells (DCs) or MHC-II in type 3 innate lymphoid cells (ILC3) resulted in abrogation of iTreg cell differentiation and in expansion, instead, of pTh17 cells in MLN and lamina propria. A similar iTreg phenotype was observed when molecules involved in TGF-β release were mutated in DCs or ILC3, suggesting that regulated local release of this iTreg-inducing cytokine requires naive T cells to interact with both DCs and ILC3.

Our first aim is to precisely characterize, through genetic and transcriptomic approaches, the cell types required for iTreg induction in the MLN, and rule out potential for misinterpretation due to expression of Cre in rare uncharacterized APCs or to indirect effects of the cell type-restricted mutations; and determine the spatiotemporal interactions of the cells, using multiphoton microscopy.

The second aim is to identify the CCR7-independent APC(s) required for pTh17 cell induction in settings of compromised iTreg induction.

The third aim is to leverage the H. hepaticus-specific system to investigate potential non-T cell priming functions of diverse MHC-II-expressing cell types in the intestinal lamina propria, including epithelial and endothelial cells.

New York University

<P>THE GOALS ARE:</P><UL><LI>TO FOSTER FUNDAMENTAL CREATIVE DISCOVERIES, INNOVATIVE RESEARCH STRATEGIES, AND THEIR APPLICATIONS AS A BASIS FOR ULTIMATELY PROTECTING AND IMPROVING HEALTH;</LI><LI>TO DEVELOP, MAINTAIN, AND RENEW SCIENTIFIC HUMAN AND PHYSICAL RESOURCES THAT WILL ENSURE THE NATION'S CAPABILITY TO PREVENT DISEASE;</LI><LI>TO EXPAND THE KNOWLEDGE BASE IN MEDICAL AND ASSOCIATED SCIENCES IN ORDER TO ENHANCE THE NATION'S ECONOMIC WELL-BEING AND ENSURE A CONTINUED HIGH RETURN ON THE PUBLIC INVESTMENT IN RESEARCH; AND</LI><LI>TO EXEMPLIFY AND PROMOTE THE HIGHEST LEVEL OF SCIENTIFIC INTEGRITY, PUBLIC ACCOUNTABILITY, AND SOCIAL RESPONSIBILITY IN THE CONDUCT OF SCIENCE.</LI></UL><P>IN REALIZING THESE GOALS, THE NIH PROVIDES LEADERSHIP AND DIRECTION TO PROGRAMS DESIGNED TO IMPROVE THE HEALTH OF THE NATION BY CONDUCTING AND SUPPORTING RESEARCH:</P><UL><LI>IN THE CAUSES, DIAGNOSIS, PREVENTION, AND CURE OF HUMAN DISEASES;</LI><LI>IN THE PROCESSES OF HUMAN GROWTH AND DEVELOPMENT;</LI><LI>IN THE BIOLOGICAL EFFECTS OF ENVIRONMENTAL CONTAMINANTS;</LI><LI>IN THE UNDERSTANDING OF MENTAL, ADDICTIVE AND PHYSICAL DISORDERS; AND</LI><LI>IN DIRECTING PROGRAMS FOR THE COLLECTION, DISSEMINATION, AND EXCHANGE OF INFORMATION IN MEDICINE AND HEALTH, INCLUDING THE DEVELOPMENT AND SUPPORT OF MEDICAL LIBRARIES AND THE TRAINING OF MEDICAL LIBRARIANS AND OTHER HEALTH INFORMATION SPECIALISTS.</LI></UL>

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

New York, New York 10016 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-25-301)

Amendment Since initial award the End Date has been extended from 02/28/26 to 06/30/31 and the total obligations have increased 513% from $521,077 to $3,196,272.