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T Cell Immunity in Giant Cell Arteritis

Award Number: R01HL142068
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2018
PERIOD OF PERFORMANCE END DATE: 05/31/2029

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T Cell Immunity in Giant Cell Arteritis - Project Summary Giant Cell Arteritis (GCA) is a granulomatous vasculitis of the aorta and its major branch vessels that causes blindness, stroke and aortic aneurysm and serves as an informative model system of immune-mediated vaso-occlusive disease. Previous work supported by this award has implicated the spontaneous failure of the PD1/PD-L1 immune checkpoint in driving excessive T cell immunity that manifests as autoimmune disease of the three-layered large elastic arteries. Recent work has extended the immune checkpoint deficiencies in GCA patients to the inhibitory CD155/CD96 checkpoint, raising the intriguing possibility that a common abnormality in inhibitory signaling unleashes autoimmunity in blood vessels. We found that macrophages (Mφ) from GCA patients lacked surface expression of the inhibitory checkpoint ligands CD155 and PD-L1, enabling the unopposed expansion of pathogenic CD4+ T cells. Lack of negative signals delivered by CD155low Mφ licensed CD4+CD96+ T cells to become tissue invasive and differentiate into IL-9 producing effector cells. Gain-of function and loss-of-function experiments identified IL9 as a key regulator in vessel wall inflammation, linking the breach of self-tolerance to the CD155- CD96-IL9 pathway. In subcellular mapping studies of GCA Mφ, the CD155 and PD-L1 protein were retained on the membranes of the endoplasmic reticulum (ER) and ER stress induced retention of the ligands, providing important clues towards the underlying molecular abnormalities. These data strongly support a “lost inhibition model” as the core abnormality in GCA. Here, we propose that GCA is a syndrome of immune checkpoint failure, and that vascular inflammation is a result of insufficient containment of antigen-reactive immune responses. Our data assign the primary defect to antigen-presenting cells which retain inhibitory checkpoint ligands in the ER. Unrestrained CD4+ T cells invade the vessel wall and misdifferentiate into vasculitogenic effector cells. To pursue this hypothesis, we will define molecular and functional abnormalities in CD155low PD-L1low Mφ; investigate the impact of ER stress on the Mφ transcriptome and proteome and map the molecular defects causing disruption of CD155 intracellular trafficking (Aim 1). Aim 2 will examine the impact of CD155low PD- L1low Mφ on T cell differentiation and functional commitment. Specifically, we will identify CD4+ T cell populations that escape from containment in the absence of CD155 and PD-L1 signaling, define their phenotypic and functional specification through CITE-Seq and examine their disease relevance in the human artery-NSG model system of GCA. This proposal aims to leverage understanding of inhibitory immune checkpoints to build new paradigms for the diagnosis and therapy of autoimmune vascular inflammation.


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 = $581,040 )
2025	2025	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cardiovascular Diseases Research	001	6	5/3/2025	NON-COMPETING CONTINUATION	$581,040
2025	2021	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cardiovascular Diseases Research	000	4	2/17/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $581,040

Issue Date FY: 2024 ( Subtotal = $581,040 )
2024	2024	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cardiovascular Diseases Research	001	5	6/10/2024	COMPETING CONTINUATION	$58,104
2024	2024	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cardiovascular Diseases Research	000	5	11/29/2023	COMPETING CONTINUATION	$522,936
														Subtotal = $581,040

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cardiovascular Diseases Research	000	4	6/22/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cardiovascular Diseases Research	002	4	10/29/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$648,592
2022	2021	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cardiovascular Diseases Research	003	4	5/26/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2022	2020	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	001	3	10/29/2021	NON-COMPETING CONTINUATION	-$392,500
2022	2019	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	000	2	10/29/2021	NON-COMPETING CONTINUATION	-$256,092
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $354,759 )
2021	2021	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cardiovascular Diseases Research	001	4	9/3/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$354,759
2021	2020	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	000	3	9/2/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $354,759

Issue Date FY: 2020 ( Subtotal = $392,500 )
2020	2020	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	000	3	6/15/2020	NON-COMPETING CONTINUATION	$392,500
														Subtotal = $392,500

Issue Date FY: 2019 ( Subtotal = $392,500 )
2019	2019	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	000	2	5/31/2019	NON-COMPETING CONTINUATION	$392,500
														Subtotal = $392,500

Issue Date FY: 2018 ( Subtotal = $392,500 )
2018	2018	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	000	1	5/18/2018	NEW	$392,500
														Subtotal = $392,500

Grand Total All Awards = $2,694,339

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T Cell Immunity in Giant Cell Arteritis

Award Number: R01HL142068

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2018

PERIOD OF PERFORMANCE END DATE: 05/31/2029

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