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Lipid Antigens for iNKT Cells in the Gut Microenvironment

Award Number: R01AI143855
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/06/2020
PERIOD OF PERFORMANCE END DATE: 01/31/2025

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Lipid Antigens for iNKT Cells in the Gut Microenvironment - Project Summary The gut microbiota is recognized as a central factor influencing immune responses. This proposal addresses two important questions in understanding how microbes regulate human health: 1) What are the microbe- derived molecules that influence immunity? 2) How does chronic exposure to microbial products alters the phenotype of immune cells in their local environment? Discovering and characterizing the molecules involved in the crosstalk between symbiont microbes and the immune system is a fundamental step towards modulating both the beneficial and harmful potential of the human-microbe relationship. The first major aspect of this project (Aims 1 and 2) uses a series of biochemical approaches to define specific bioactive microbial lipids from human-derived gut microbes that activate invariant natural killer T (iNKT) cells, a specialized lymphocyte subset that recognizes specific lipids as antigens and orchestrates immune responses in multiple contexts. Although animal models have uncovered a role for iNKT cells in immunity, the lipid antigens that they recognize remain unknown in most situations. Here, we study two human symbiont microbes that produce iNKT cell-activating lipids, an uncommon feature among gut anaerobes. To identify the specific molecular lipid species that activate iNKT cells, we will use a newly-developed method, the “T cell receptor trap,” to capture antigenic lipids. Once purified, these lipids will be characterized by mass spectrometry, including new methods that distinguish sugar stereochemistry, which is of central importance to the activity of lipids that activate iNKT cells. The second major aspect of this project (Aim 3) builds on preliminary transcriptomic data to investigate how chronic exposure to lipid antigens affects the phenotype of iNKT cells in the gut in a mouse model. Since iNKT cells orchestrate immune responses in many situations, and can be either beneficial and harmful, changes to their phenotype in the gut is likely to alter the course of enteral infection, inflammatory bowel disease, colon cancer, or food allergy. To understand how lipids in the gut regulate iNKT cell populations, we will use two reductionist models, feeding mice with experimental diets containing different levels of iNKT cell lipid antigens, or colonization of germ-free mice with lipid antigen-producing microbes. In these models, we will perform high- depth phenotyping of the gut iNKT cell populations. Together, these studies will define lipid antigens from two important members of the human gut microbiota and shed light on the mechanisms by which gut lipid antigens shape iNKT cell populations.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	5	5/8/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $403,260 )
2024	2024	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	5	12/14/2023	NON-COMPETING CONTINUATION	$362,934
2024	2024	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	001	5	5/24/2024	NON-COMPETING CONTINUATION	$40,326
														Subtotal = $403,260

Issue Date FY: 2023 ( Subtotal = $403,260 )
2023	2023	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	4	12/20/2022	NON-COMPETING CONTINUATION	$403,260
														Subtotal = $403,260

Issue Date FY: 2022 ( Subtotal = $403,260 )
2022	2022	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	3	1/25/2022	NON-COMPETING CONTINUATION	$403,260
														Subtotal = $403,260

Issue Date FY: 2021 ( Subtotal = $403,260 )
2021	2021	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	2	2/3/2021	NON-COMPETING CONTINUATION	$403,260
														Subtotal = $403,260

Issue Date FY: 2020 ( Subtotal = $403,260 )
2020	2020	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	1	2/6/2020	NEW	$403,260
														Subtotal = $403,260

Grand Total All Awards = $2,016,300

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Lipid Antigens for iNKT Cells in the Gut Microenvironment

Award Number: R01AI143855

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 02/06/2020

PERIOD OF PERFORMANCE END DATE: 01/31/2025

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