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.