Tuesday, May 13, 2025 5/13/2025

Role of secreted phospholipase A2 in the activation of human CD1-restricted T cells

Award Number: R01AR074037
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

Group Awards By:

View Award Description

Role of secreted phospholipase A2 in the activation of human CD1-restricted T cells - PROJECT SUMMARY CD1 proteins are structurally related to MHC class I, but instead of peptides, they present lipid antigens to T cells. We and others have shown that CD1-restricted T cells recognizing self-lipids are abundant in the human T cell repertoire, yet it remains unclear how the activation of these T cells is regulated in vivo. Overt reactivity to self-lipids suggests that antigenic CD1-lipid complexes must be tightly regulated in order to prevent continuous T cell stimulation. Both fatty acids and lysophosphatidylcholine (LPC) have been identified as antigens for certain human CD1-restricted T cells. These lipids are released when the enzyme phospholipase A2 (PLA2) acts on membrane phospholipids, supporting a role for PLA2 activity in the generation of CD1 self antigens. Since secreted PLA2 (sPLA2) is increased in response to tissue damage and infections, we hypothesize that sPLA2 activity in humans is a common mechanism through which the activation of CD1-restricted T cells is regulated, by temporarily increasing the availability of CD1 self-lipid antigens. This is supported by our preliminary observations that PLA2 activity on antigen presenting cells results in CD1-dependent T cell activation in healthy individuals. Furthermore, since sPLA2 levels are constitutively elevated in many chronic inflammatory conditions, including rheumatoid arthritis, asthma, atherosclerosis and psoriasis, this mechanism may underlie persistent T cell activation in these conditions through continued high levels of self lipid antigens. In this proposal we will systematically investigate the link between sPLA2 activity and activation of lipid-specific T cell populations, and characterize the human CD1-restricted T cell populations that respond to PLA2-derived phospholipid breakdown products. Using T cell cultures and a human skin explant model, we will determine if PLA2 activity induces the activation/expansion of lysophospholipid-reactive T cell populations. We will investigate the breadth of the human lysophospholipid-specific T cell repertoire, and its specificity/promiscuity. For this we use a panel of lysophospholipid-loaded CD1 tetramers, and a CD1 plate assay. Last, we will apply combined single cell TCR sequencing and functional phenotyping to CD1-LPC tetramer+ T cells isolated from healthy donors and psoriasis patients, to determine if these populations primarily have pro-inflammatory or immunoregulatory functions, and whether clonal expansions occur in the context of inflammatory skin disease. This proposal will provide insight in whether sPLA2 activity is a significant driver of human CD1-restricted T cell activation, and will elucidate the specificities and functions of the responding T cell populations. Because sPLA2 activity is central to both acute and chronic inflammation, results from this study will lead to a better understanding of a common physiological pathway through which T cells can be activated in multiple distinct inflammatory conditions, and provide novel insights in modes through which lipid-specific T cell activation may be regulated therapeutically.


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: 2024 ( Subtotal = $345,708 )
2024	2024	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	5	6/10/2024	NON-COMPETING CONTINUATION	$24,948
2024	2024	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	11/30/2023	NON-COMPETING CONTINUATION	$320,760
2024	2024	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	5	9/11/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $345,708

Issue Date FY: 2023 ( Subtotal = $356,400 )
2023	2023	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	12/6/2022	NON-COMPETING CONTINUATION	$320,760
2023	2023	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	4	2/22/2023	NON-COMPETING CONTINUATION	$35,640
														Subtotal = $356,400

Issue Date FY: 2022 ( Subtotal = $320,760 )
2022	2022	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	11/18/2021	NON-COMPETING CONTINUATION	$320,760
														Subtotal = $320,760

Issue Date FY: 2021 ( Subtotal = $345,708 )
2021	2021	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	2	7/20/2021	NON-COMPETING CONTINUATION	$24,948
2021	2021	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	12/2/2020	NON-COMPETING CONTINUATION	$320,760
														Subtotal = $345,708

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2019	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	5/1/2020	NEW	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $356,400 )
2019	2019	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	3/11/2019	NEW	$356,400
														Subtotal = $356,400

Grand Total All Awards = $1,724,976

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Role of secreted phospholipase A2 in the activation of human CD1-restricted T cells

Award Number: R01AR074037

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer