NKT cells are innate-like T cells and tend to reside in non-lymphoid tissues and to have markers of chronically activated or memory cells. When activated, NKT cells exhibit a fast and more robust effector function such as cytokine release or cytotoxicity. They are thought to serve as a bridge between the rapidly occurring innate immunity and the more slowly occurring adaptive immunity. Thymus-derived NKT cells undergo further differentiation and functional specialization in the periphery that promotes their migratio into non-lymphoid tissues such as the liver and adipose tissue. Therefore, NKT cells are a heterogeneous population with a high degree of phenotypic and functional specialization in non-lymphoid tissues. The recent studies in different clinical and experimental settings showed that while NKT cells are more often pathogenic, they are also regulatory. NKT cells are abundant in the liver and adipose tissue, two organs that play a critical role in the development of metainflammation. Recently, the signaling pathways that control cellular metabolism have been shown to have a crucial role in dictating the outcome of T cell activation and effector function. Distinct T cell subsets adopt metabolic programs specific to support their needs. Upon T cell activation, reactive oxygen species (ROS) is produced by mitochondria, which is required for T-cell activation. Substantial evidence has revealed that ROS are essential second messengers in innate and adaptive immune cells. Yet increased levels of ROS within immune cells can result in hyperactivation of inflammatory responses, resulting in tissue damage and pathology. Although much effort has put forth to understand metabolic needs and regulation of CD4 and CD8 T cells, little is known about the metabolic regulation of NKT cells. Our preliminary studies showed that freshly isolated NKT cells from the liver have high ROS than CD4 T cells, whereas NKT cells resident in visceral adipose tissue show low ROS similar to CD4 T cells. Interestingly, NKT cells in these two tissues have an opposing function. Based on the published studies and our preliminary data, we hypothesize that the breakdown of tolerance of cell metabolism of NKT cells leads to inflammation and tissue damage resulting in autoimmune hepatitis and obesity. To test the hypothesis, we will investigate the metabolic regulation in NKT cells and how cell metabolism of NKT cells regulates two distinct metabolic immune diseases, liver inflammation and obesity. Given the importance of NKT cells as a critical factor for immune diseases, studying the regulation of cell metabolism, oxidative stress and immune diseases mediated by NKT cells is highly innovative and significant.

Public Health Relevance

The proposed research is relevant to public health because a better understanding of innate T lymphocyte development and function is expected which will help us design therapies and treatments of various immune diseases. Thus, the proposed research is relevant to the part of NIH's mission that pertains to pursuit of fundamental knowledge about the nature and behavior of human health systems.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI121156-03
Application #
9387371
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Mallia, Conrad M
Project Start
2015-12-10
Project End
2020-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Shen, Hong; Sheng, Liang; Xiong, Yi et al. (2017) Thymic NF-?B-inducing kinase regulates CD4+ T cell-elicited liver injury and fibrosis in mice. J Hepatol 67:100-109
Kim, Yeung-Hyen; Kumar, Ajay; Chang, Cheong-Hee et al. (2017) Reactive Oxygen Species Regulate the Inflammatory Function of NKT Cells through Promyelocytic Leukemia Zinc Finger. J Immunol 199:3478-3487
Pyaram, Kalyani; Sen, Jyoti Misra; Chang, Cheong-Hee (2017) Temporal regulation of Wnt/?-catenin signaling is important for invariant NKT cell development and terminal maturation. Mol Immunol 85:47-56