In both humans and mice, Foxp3+ regulatory T (Treg) cells are required to suppress self-reactive T cells and prevent autoimmunity. In addition to this suppressor function, Treg cells are also present in non-lymphoid tissues, where they may utilize distinct transcriptional programs to perform tissue-specific functions. However, a molecular understanding of tissue Treg development and function remains elusive. To address the properties and functions of Treg cells in non-lymphoid tissues, I have examined the transcriptome of hepatic Treg cells by RNA sequencing. By comparing highly expressed genes in hepatic Treg cells to previously generated gene expression data of Treg cells from adipose tissue and colon, I have identified the nuclear receptor ROR? as being enriched in Treg cells from these three peripheral tissues. Subsequently, I will define the role of ROR? in Treg cells by extensively characterizing conditional knockout mice in which Treg cells lack ROR?. I will use genetic tools and a candidate approach to identify the molecular signals that regulate ROR? expression, and RNA sequencing to identify the genes regulated by ROR? in Treg cells. Using the liver as a model organ for its unique capacity for regeneration, I will examine the role of Tre cells in the setting of necro-inflammatory liver damage versus compensatory hyperplasia. I will use conditional knockout mice in which Treg cells lack ROR? or other tissue-Treg-specific molecules, or Foxp3DTR mice in which Treg cells can be depleted, to determine the functional significance of Treg cells in tissue repair. Tissue Treg cells are an attractive candidate for immunomodulation in the therapy of many autoimmune, infectious, metabolic, and neoplastic diseases. By advancing basic knowledge of the mechanisms governing tissue Treg function, the proposed research may reveal novel strategies for immunotherapy.

Public Health Relevance

This project will improve our understanding of the functions of regulatory T (Treg) cells in non-lymphoid tissues such as the liver. Specifically, I will use genetc tools to address the hypothesis that tissue-resident Treg cells are specialized to survive in tissues, where they function in surveillance and repair. This will inform our ability to manipulate tissue Treg cells in the treatment of autoimmune diseases or cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30AI122721-03
Application #
9405832
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Gondre-Lewis, Timothy A
Project Start
2016-01-07
Project End
2019-03-06
Budget Start
2018-01-07
Budget End
2019-01-06
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Administration
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
Adams, Nicholas M; Lau, Colleen M; Fan, Xiying et al. (2018) Transcription Factor IRF8 Orchestrates the Adaptive Natural Killer Cell Response. Immunity 48:1172-1182.e6
Fan, Xiying; Moltedo, Bruno; Mendoza, Alejandra et al. (2018) CD49b defines functionally mature Treg cells that survey skin and vascular tissues. J Exp Med 215:2796-2814
Fan, Xiying; Rudensky, Alexander Y (2016) Hallmarks of Tissue-Resident Lymphocytes. Cell 164:1198-1211
Chinen, Takatoshi; Kannan, Arun K; Levine, Andrew G et al. (2016) An essential role for the IL-2 receptor in Treg cell function. Nat Immunol 17:1322-1333
Stamatiades, Efstathios G; Tremblay, Marie-Eve; Bohm, Mathieu et al. (2016) Immune Monitoring of Trans-endothelial Transport by Kidney-Resident Macrophages. Cell 166:991-1003
O'Sullivan, Timothy E; Rapp, Moritz; Fan, Xiying et al. (2016) Adipose-Resident Group 1 Innate Lymphoid Cells Promote Obesity-Associated Insulin Resistance. Immunity 45:428-41