Thursday, November 21, 2024 11/21/2024

Regulation of dermal gammadelta T cells by microbial pathogens/commensals in health and psoriasis

Award Number: R01AI128818
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary Psoriasis is one of the most common immune-related chronic inflammatory skin disorders. Clinical observations suggest that streptococcal infection has an intimate relationship in triggering psoriasis onset and exacerbating chronic psoriasis. Humanized IL-12/IL-23 p40, IL-17A, and IL-17 receptor mAbs have shown remarkable therapeutic efficacy for the treatment of chronic plaque psoriasis, suggesting IL-23/IL-17 axis plays important roles in psoriasis pathogenesis. Our previous studies have demonstrated that dermal γδ T cells are the major IL-17 producers in the skin and are critical in psoriasis pathogenesis. Dermal γδ T cells are phenotypically and functionally unique. However, it is largely unknown how these cells are critically regulated in mice and humans, particularly in the context of microbial infection and skin microbial commensal alteration. In the proposal, we provided preliminary data suggesting that dermal γδ T cells play critical roles in skin immune surveillance and inflammation. IL-1β signaling pathway plays a crucial role in regulating dermal γδ T cell proliferation, IL-17 production, and probably trafficking in mice. Pathogen products stimulated skin cells to produce IL-1β. In addition, we showed that skin microbiota from psoriatic skin has been substantially altered compared to that in healthy control skin. Human Vγ9Vδ2 T cells were capable of secreting IL-17 and significantly decreased in the peripheral blood of psoriatic patients but increased in psoriatic skin lesions and produced large amounts of IL-17. Based on these preliminary findings, we hypothesize that dysregulated dermal γδ T cells via IL-1 signaling by pathogen infection or skin microbiota alteration play an essential role in psoriasis pathogenesis. Three Aims are proposed to address this hypothesis. Aim 1 determines the role of IL-1 signaling in psoriasis immunopathogenesis. We will test the hypothesis that IL-1 signaling regulates psoriasis immunopathogenesis through 1) directly activating dermal γδ T cells; 2) stimulating KC to secrete chemokines which chemoattract more IL-17-producing γδ T cells from periphery into dermis thus amplifying skin inflammatory cascade; 3) generating memory-like dermal γδ T cells for disease relapse. Aim 2 examines how skin commensal microorganisms regulate dermal γδ T cell homeostasis in healthy skins and dermal γδ T cell activation in skin inflammation. Aim 3 determines how human Vγ9 T cells are regulated by pathogen components or skin microbiota alteration for expansion and IL-17 production. Human skin/SCID mouse xenograft model will be established to determine the pathogenic roles of human Vγ9 T cells and microbial infection/commensal alteration in psoriasis pathogenesis. It is believed that this study will provide new insights into understanding the biology of dermal γδ T cell population and immuno-pathogenesis of psoriasis.


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	2021	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Allergy and Infectious Diseases Research	000	5	10/29/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Allergy and Infectious Diseases Research	000	5	3/20/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $189,495 )
2021	2021	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Allergy and Infectious Diseases Research	000	5	3/19/2021	NON-COMPETING CONTINUATION	$189,495
														Subtotal = $189,495

Issue Date FY: 2020 ( Subtotal = $192,238 )
2020	2020	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Allergy and Infectious Diseases Research	000	4	3/16/2020	NON-COMPETING CONTINUATION	$192,238
														Subtotal = $192,238

Issue Date FY: 2019 ( Subtotal = $194,902 )
2019	2019	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Allergy and Infectious Diseases Research	000	3	3/13/2019	NON-COMPETING CONTINUATION	$194,902
														Subtotal = $194,902

Issue Date FY: 2018 ( Subtotal = $197,488 )
2018	2018	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Allergy and Infectious Diseases Research	000	2	3/27/2018	NON-COMPETING CONTINUATION	$197,488
														Subtotal = $197,488

Issue Date FY: 2017 ( Subtotal = $200,000 )
2017	2017	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Allergy and Infectious Diseases Research	000	1	4/14/2017	NEW	$200,000
														Subtotal = $200,000

Grand Total All Awards = $974,123

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Regulation of dermal gammadelta T cells by microbial pathogens/commensals in health and psoriasis

Award Number: R01AI128818

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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