The goal of this project is to understand the mechanisms that control effector lymphocyte stability and plasticity, and how this regulation influences human health and disease. Recent studies indicate that innate lymphocytes possess substantial plasticity. The underlying mechanisms, and the implications for health and disease, remain unknown. Our preliminary data indicate that exposure to Notch signaling can elicit innate lymphocyte plasticity and train mature group-2 innate lymphoid cells (ILC2) to acquire the ability to co-produce large amounts of both ILC2- and ILC3- characteristic cytokines, thus converting natural ILC2 (nILC2) into plastic inflammatory ILC2 (iILC2). Our new data suggest that such plastic iILC2 are relatively enriched in the airway of patients with severe refractory asthma. In this project, we will use adoptive transfer, chromatin immunoprecipitation, and RNA sequencing experiments to explore the cellular and molecular mechanisms by which Notch signaling elicits ILC2 plasticity. We will also examine the capability of human and mouse iILC2 to mediate airway inflammation and hyperresponsiveness. Finally, we will investigate the association between the development of plastic iILC2 and the susceptibility to severe refractory asthma in human adult patients. Together, these experiments will shed light on the mechanisms that govern lymphocyte lineage stability and plasticity, and will inform strategies of targeted therapy to treat patients with asthma and other auto-immune and inflammatory disorders.

Public Health Relevance

This project aims at understanding the development and function of inflammatory innate lymphoid cells in severe refractory asthma. Our work will shed light on the mechanisms that control effector lymphocyte stability and plasticity, and may also inform strategies to combat severe refractory asthma and other immune and inflammatory disorders.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL137813-01A1
Application #
9519366
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Lachowicz-Scroggins, Marrah Elizabeth
Project Start
2018-04-15
Project End
2022-03-31
Budget Start
2018-04-15
Budget End
2019-03-31
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Albany Medical College
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
190592162
City
Albany
State
NY
Country
United States
Zip Code
12208