PD-L1 back signaling manipulates IL-6 signaling to coordinate innate immune responses

Abstract

Abstract Programmed death ligand-1 (PD-L1) interaction with PD-1 on T cells limits immune activation to prevent immunopathology in healthy tissues and the development of autoimmunity. While ligation of PD-1 by PD-L1 leads to T cell-intrinsic PD-1 signaling, PD-L1 back signaling into the ligand-bearing cell remains poorly defined. We recently outlined a major role for PD-L1 back signaling in regulating dermal dendritic cell (DC) migration to the lymph node following a type I interferon inducing stimulus or infection. Similar to prior studies in IFNβ treated cancer cells, we noted increased pSTAT3 post DC activation that was unchanged with addition of CCL21. Increased pSTAT3 occurred in Pdl1−/− DCs and in DCs from mice in which 3 cytoplasmic residues were mutated to alanine (Pdl1CM). Since STAT3 propagates signalling through the IL-6 receptor, we hypothesized that increased IL-6 signaling may explain elevated pSTAT3 in Pdl1−/− and Pdl1CM DCs. To test whether PDL1 back signaling contributed to STAT3-associated cytokine responses, we generated bone marrow derived DCs from Pdl1−/− and Pdl1CM mice and observed significantly higher levels of IL-6 compared to WT controls following activation. We next asked if PD-L1 back signaling is important for proper innate activation as PD-L1 is upregulated on many innate immune populations early after systemic L. monocytogenes (LM) infection. We found loss of PD-L1 back signaling following infection led to differences in circulating levels of many innate immune cells and reduced IL-6 in the serum. These findings demonstrate that PD-L1 back signaling in innate immune cells may assist in coordinating IL-6 signaling and proper activation of early innate immune responses during systemic LM infection. Supported by grants from NIH (R01 AI155474, T32 AI074491 - "Molecular Mechanisms of Immune Tolerance")