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Cholesterol metabolites coordinate skin barrier immunity centered on innate dermal gammadelta T cells programmed to produce IL-17

Award Number: R01AI158832
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Summary Immunological control of mucosal barrier development and maintenance is a critical process, as imbalances in immune sentinel activity can lead to skin, lung and gut inflammatory diseases. Central in the mucosal tissue homeostasis are type 3 cytokine producing lymphocytes. Cytokines, cytokines receptors and master transcriptions involved in tissue development and barrier fortification have been identified based on analyses of loss of function models in human and mice. However, non-inflammatory factors that orchestrate the type 3 responses in tissues to assure proper immune reactions and prevent aberrant inflammation have not been well characterized. We discovered that oxysterols, a major class of cholesterol metabolites with established immunomodulatory activities, are the primary positional cues for the stereotypical type 3 lymphocytes in the skin called T¿d17 cells. Ebi2 (encoded by Gpr183) is the G protein coupled receptor (GPCR) that senses specific types of oxysterols, and is expressed on all type 3 cytokine producing lymphocytes. Increased dietary cholesterol enhances Tgd17 activity at the skin interface via augmented oxysterol production and sensing. However, how tissue resident cells contribute to the anatomical framework that generate the final positional cues for dermal IL-17 secreting innate T lymphocytes is not known. Moreover, whether oxysterols are involved in the development of skin-tropic Tgd17 and other type 3 cytokine producing lymphocytes is not known. In this project we will test the hypothesis that Tgd17 cells maintain barrier tissue homeostasis by sensing cues that reflect nutritional states and inputs from the peripheral nerve system. Metabolic changes in the epithelial- neuronal niche in the skin control optimal microanatomical Tgd17 positioning and function via GPR183. This integrated sensory mechanism for cholesterol metabolism and neuronal inputs is imprinted early in T¿d17 thymocyte maturation through interactions with a novel subset of thymic epithelial cells programmed to produce oxysterols. The conceptual basis of this project is innovative as there are no precedents for the oxysterol- regulated mucosal tissue hub integrating epithelial-neuronal-immune communications critical for barrier tissue fitness.


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 = $637,049 )
2024	2024	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Allergy and Infectious Diseases Research	000	3	10/30/2023	NON-COMPETING CONTINUATION	$637,049
														Subtotal = $637,049

Issue Date FY: 2023 ( Subtotal = $707,833 )
2023	2023	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Allergy and Infectious Diseases Research	000	2	10/31/2022	NON-COMPETING CONTINUATION	$707,833
														Subtotal = $707,833

Issue Date FY: 2022 ( Subtotal = $703,646 )
2022	2022	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Allergy and Infectious Diseases Research	000	1	10/25/2021	NEW	$703,646
														Subtotal = $703,646

Grand Total All Awards = $2,048,528

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Cholesterol metabolites coordinate skin barrier immunity centered on innate dermal gammadelta T cells programmed to produce IL-17

Award Number: R01AI158832

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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