Only recently has the extent of the diversity of innate immune effector functions become apparent, with the discovery of multiple novel subtypes of innate lymphoid cells (ILCs), beyond long recognized natural killer cells. ILCs have been classified into group 1 (ILC1), group 2 (ILC2), and group 3 (ILC3), on the basis of their effector cytokine secretion profile and expression of key transcriptional regulators, although there is diversity within each group. Here we have focused on ILC2 cells in the lung. ILC2 cells play a complex role in lung immunity, functioning as part of the protective immune response to parasites and supporting epithelial cell repair following viral infection, but also stimulating TH2 responses, and contributing to allergic inflammation themselves by secretion of type 2 cytokines. However, whether ILC2 cells can also develop into anti-inflammatory effector cells is not known. We used whole transcriptome analysis to ask whether a subset of murine ILC2 cells with regulatory potential might be generated upon activation. This has led to the discovery of a subpopulation of lung ILC2 cells that can express IL-10 upon in vivo activation with the `alarmin' IL-33. Other genes encoding immunomodulatory cell surface proteins are also induced. IL-10 has emerged as a key player in limiting inflammatory responses, including in the context of allergic diseases. While ILC2 cells are potent producers of cytokines that are critical in the pathophysiology of allergic disease, there is no method currently available to specifically inhibit the function of ILC2 cells without also targeting other effector cells. Understanding the signals t induce generation and activation of a regulatory population of ILC2 cells that might ameliorate inflammation could allow development of novel therapeutic modalities involving these cells. These foundational series of studies will explore the requirements for induction of an IL-10 response from lung ILC2 cells, test the ability of these cells to mediate or suppress an inflammatory response, and analyze the IL-10+ ILC2 cell transcriptome. Specifically, using IL-10 reporter mice, we will analyze the kinetics and cellular composition of the lung IL-10 response to IL-33, including ILC2 cells. In addition, we will examine expression of other coinhibitory cell surface molecules. The requirements to induce an IL-10 response from ILC2 cells is not known, and we will address this in vivo and in vivo, identifying cell types and cytokines that are involved. We hypothesize that IL-10+ ILC2 cells are anti-inflammatory, and adoptive transfer of ILC2 cells into hosts challenged with IL-33 or protease allergen papain will directly test this idea. Finally, using RNA-seq we will compare the transcriptome of activated IL-10- and IL-10+ ILC2 cells from lungs of IL-33 injected reporter mice to characterize the molecular signature of these cells, look for biomarkers of these effector cells, and obtain additional clues as to function.

Public Health Relevance

Over the last five years, a diverse collection of immune cells, called innate lymphoid cells, has been identified. These cells play key roles in immunity, but have also been implicated in the pathology of lung allergic diseases. This research project is directed at characterization of a novel subset of these cells in the lung that may have anti-inflammatory properties, and thus might have potential to suppress allergic responses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI124209-01
Application #
9101728
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Davidson, Wendy F
Project Start
2016-02-12
Project End
2018-01-31
Budget Start
2016-02-12
Budget End
2017-01-31
Support Year
1
Fiscal Year
2016
Total Cost
$262,500
Indirect Cost
$112,500
Name
Cedars-Sinai Medical Center
Department
Type
DUNS #
075307785
City
Los Angeles
State
CA
Country
United States
Zip Code
90048