Cell Intrinsic Programmed Death-Ligand 1 (PD-L1) Signaling Limits Low Affinity T cell Responses during Acute Infection with Listeria Monocytogenes 2306749

Abstract Introduction Programmed Death-1 (PD-1)/Programmed Death-Ligand 1 (PD-L1) signaling through the extracellular domain is responsible for T cell downregulation following acute infection and prevents excessive tissue damage. Although the role of extracellular PD-1/PD-L1 signaling is well defined during infection, signaling via the cytoplasmic domain, termed PD-L1 intrinsic signaling, is less understood. Utilizing a novel mouse model containing mutations in the cytoplasmic tail of PD-L1 (Pdl1CyMt), our lab defined that bone marrow-derived dendritic cells (BMDCs) obtained from Pdl1CyMt mice exhibit heightened activation compared to control BMDCs following treatment with TLR agonists. Methods To investigate if heightened DC activation leads to exacerbated T cell responses, we infected control and Pdl1CyMt mice with Listeria monocytogenes (Lm). Pdl1CyMt mice exhibit decreased liver pathology at day 7 post infection (p.i.) compared to control mice, and increased CD8+ T cell cytokine production. To address if increased CD8+ T cell responses resulted from lower affinity T cells responding in the Pdl1CyMt mice we infected mice with Lm expressing H2-Kb peptides of OVA with altered amino acids (altered peptide ligands) that bind MHCI equally but vary in their ability to stimulate OT-I cells. Results We found that in Pdl1CyMt mice, OT-I CD8+ T cells expanded more to low-affinity ligands compared to controls and displayed reduced tissue pathology. Conclusion These data suggest that intrinsic PD-L1 signaling decreases the threshold of activation for lower affinity T cell responses and limits liver pathology associated with Lm infection. Intriguingly, Pdl1CyMt mice exhibit enhanced bacteremia at day 7 when control mice have cleared the infection. These studies suggest that both the intracellular and extracellular domain of PD-L1 contribute to tissue specific responses that modulate T cell activation. Funding Source n/a Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)