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Programmed death ligand-1 interactions in the regulation of dendritic cell migration and T cell priming

Award Number: F30AI176607
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 12/01/2023
PERIOD OF PERFORMANCE END DATE: 11/30/2027

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Programmed death ligand-1 interactions in the regulation of dendritic cell migration and T cell priming - PROJECT SUMMARY/ABSTRACT: Dendritic cells (DCs) are sentinels of the immune system that operate at interface of the innate and adaptive immune response. DC-driven responses require their migration from peripheral tissue to the draining lymph node in order prime naïve T cells. Understanding and discovering novel targets that can manipulate DC localization will be beneficial for developing new therapeutic interventions, particularly in the context of vaccination where DC-driven responses are critical for initiation of memory T cell responses. Programmed death ligand-1 (PD-L1) and CD80 are cell-surface protein ligands that belong to the B7 family of proteins and possess the ability to bind to the CD28 family of receptors on T cells in order to provide coinhibitory or costimulatory signals. In addition to their roles in cell-cell communication between DCs and T cells, how PD-L1 and CD80 regulate intracellular signals within migratory DCs remains understudied. Recent published work from the laboratory of my mentor, Dr. Beth Tamburini, demonstrated that PD-L1 intracellular signaling plays an important role in regulating DC migration by controlling chemokine receptor signaling in the context of a type I immune response. My preliminary data suggest that blocking extracellular interactions of PD- L1 with CD80, but not PD-1, decreases DC migration during an inflammatory response within the skin. Additionally, I also found that increased amounts of pathogen-specific tissue resident memory T cells (TRM) persist in the skin after resolution of vaccinia infection in mice with impaired PD-L1 intracellular signaling within cross-presenting DCs. With these preliminary findings in mind, we hypothesize that PD-L1 cis interactions with CD80 regulate intracellular signaling cascades needed to promote migration of DCs. We also hypothesize that while PD-L1-mediated DC retention during cutaneous infection leads to enhanced formation of TRM cells, persistent antigen presentation leads to T cell exhaustion and impaired cell-mediated immunity upon rechallenge. Our aims are as follows: 1. Define which extracellular interactions between PD-L1 and CD80 regulate DC migration and 2. Determine how PDL1 intracellular signals facilitate memory T cell phenotype and function during a viral infection. These studies present an opportunity to investigate the mechanism by which PD-L1 governs migration of cDCs and characterize how retention of migratory DCs in the skin can alter T cell responsiveness to viral antigen. These findings are especially significant in the context of PD-L1 immunotherapy, currently used in the clinic, which prohibits both cis and trans PD-L1 interactions. Loss of these interactions by PD-L1 binding partners could explain resulting off-target effects within nonlymphoid organs such the skin in patients on PD-L1 immunotherapy.


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: 2026 ( Subtotal = $55,114 )
2026	2026	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Allergy and Infectious Diseases Research	001	3	4/15/2026	NON-COMPETING CONTINUATION	$576
2026	2026	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Allergy and Infectious Diseases Research	000	3	12/8/2025	NON-COMPETING CONTINUATION	$54,538
														Subtotal = $55,114

Issue Date FY: 2025 ( Subtotal = $38,910 )
2025	2025	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Allergy and Infectious Diseases Research	000	2	11/22/2024	NON-COMPETING CONTINUATION	$38,346
2025	2025	THE REGENTS OF THE UNIV. OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Allergy and Infectious Diseases Research	001	2	8/1/2025	NON-COMPETING CONTINUATION	$564
														Subtotal = $38,910

Issue Date FY: 2024 ( Subtotal = $37,903 )
2024	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Allergy and Infectious Diseases Research	003	1	5/8/2024	NEW	$1,280
2024	2024	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Allergy and Infectious Diseases Research	002	1	12/22/2023	NEW	$0
2024	2024	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Allergy and Infectious Diseases Research	000	1	11/30/2023	NEW	$36,623
2024	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Allergy and Infectious Diseases Research	001	1	11/30/2023	NEW	$0
														Subtotal = $37,903

Grand Total All Awards = $131,927

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Programmed death ligand-1 interactions in the regulation of dendritic cell migration and T cell priming

Award Number: F30AI176607

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 12/01/2023

PERIOD OF PERFORMANCE END DATE: 11/30/2027

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