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Interferon regulation of gamma delta intraepithelial lymphocyte activation

Award Number: R01DK119349
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2023
PERIOD OF PERFORMANCE END DATE: 04/30/2025

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Interferon regulation of gamma delta intraepithelial lymphocyte activation - PROJECT SUMMARY. Immune surveillance at mucosal barriers is essential to provide an immediate defense against invasive microbes, yet must also be tightly regulated limit the potential for autoimmunity. Intraepithelial lymphocytes expressing the γδ T cell receptor (γδ IEL) bridge innate and adaptive immunity, and function as a first line of defense by promoting mucosal barrier integrity. Recent reports demonstrate that basal γδ IEL function is influenced by extrinsic microbial signals. Although commensal-induced tonic type I interferon (IFN) signaling has been shown to prime mucosal innate immunity and host responsiveness to pathogen, the involvement of type I IFN in γδ IEL activation and epithelial surveillance remains unknown. Our preliminary data demonstrate that constitutive low level type I IFN signaling regulates the appropriate number and proportion of Vγ TCR subsets in the epithelial compartment and maintain these cells in an actively patrolling, yet immunologically quiescent state. We now show that impaired interferon α/β receptor (IFNAR) activation induces a dysregulated γδ IEL phenotype, characterized by hyperproliferation, hypermotility and enhanced IL-4 expression. Further, we find that pathogen-associated levels of type I IFN amplify γδ IEL effector functions, including epithelial surveillance. Therefore, we propose to interrogate the mechanism by which tonic type I IFN signaling maintains γδ IEL homeostasis, whereas amplification of type I IFN in response to pathogen enhances γδ IEL effector function. In the first aim, we will take advantage of genetic models that permit the inducible γδ T-cell-specific deletion of IFNAR to examine the role of tonic IFNAR/STAT signaling in the maintaining γδ IEL homeostasis through appropriate regulation of different Vγ subsets. We will also investigate the mechanisms by which IFNAR signaling regulates crosstalk between different γδ IEL subsets and how this influences the proliferation, motility and effector function of these cells. Next, we will determine the functional consequence of γδ IEL dysregulation on epithelial barrier integrity under steady-state conditions. In the second aim, we will examine the mechanisms by which type I IFN amplifies γδ IEL effector function following viral infection. Using the novel intravital microscopy techniques that we pioneered and our ability to move fluidly between in vitro and in vivo models, we will investigate the molecular signals induced by pathogen-associated levels of type I IFN to enhance γδ IEL epithelial surveillance and activation. Lastly, based on the protection conferred by γδ IELs in response to enteric pathogens, we will examine the role of type I IFN-induced γδ IEL activation in the context of acute enteric viral infection. By combining, temporal and cell-specific gene targeting, cutting edge live imaging techniques, and novel models to analyze γδ IEL function ex vivo, we expect to define the molecular mechanisms by which type I IFN regulates γδ IELs under homeostatic conditions and during infection. The proposed studies will provide new insight into the molecular mechanisms that regulate γδ IEL activation and the extent to which enhanced γδ IEL effector function affects epithelial integrity and host defense.


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 = $0 )
2024	2023	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	3/14/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$88,691
2024	2022	RUTGERS, THE STATE UNIVERSITY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	3/14/2024	NON-COMPETING CONTINUATION	-$88,691
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $379,301 )
2023	2023	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	7/3/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$379,301
2023	2022	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	6/30/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $379,301

Issue Date FY: 2022 ( Subtotal = $352,631 )
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	4/5/2022	NON-COMPETING CONTINUATION	$352,631
														Subtotal = $352,631

Issue Date FY: 2021 ( Subtotal = $352,631 )
2021	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	4/22/2021	NON-COMPETING CONTINUATION	$352,631
														Subtotal = $352,631

Issue Date FY: 2020 ( Subtotal = $352,631 )
2020	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	4/3/2020	NON-COMPETING CONTINUATION	$352,631
														Subtotal = $352,631

Issue Date FY: 2019 ( Subtotal = $352,631 )
2019	2019	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	6/4/2019	NEW	$352,631
														Subtotal = $352,631

Grand Total All Awards = $1,789,825

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Interferon regulation of gamma delta intraepithelial lymphocyte activation

Award Number: R01DK119349

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2023

PERIOD OF PERFORMANCE END DATE: 04/30/2025

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