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

Active Project Grant Awarded Last action

Award ID
F30AI176607
Recipient
Awarding agency
Obligated
$375,434

Award facts

Assistance listing
93.855 Allergy and Infectious Diseases Research
Completion date 69% complete
Place of performance
Aurora, CO 80045, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

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.

Transactions

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Quick answers

Who received award F30AI176607?

F30AI176607 was awarded to The Regents Of The University Of Colorado by National Institute of Allergy and Infectious Diseases (National Institutes of Health) on May 30, 2024.

How much is award F30AI176607 worth?

$375,434 has been obligated on F30AI176607.

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