Type 1 IFN and PD-L1 Coordinate Lymphatic Endothelial Cell Expansion and Contraction during an Inflammatory Immune Response

Lymph node (LN) expansion during an immune response is a complex process that involves the relaxation of the fibroblastic network, germinal center formation, and lymphatic vessel growth. These processes require the stromal cell network of the lymph node to act deliberately in order to accommodate the influx of immune cells to the lymph node. The molecular drivers of these processes are not well understood. Therefore, we asked whether the immediate cytokines, type 1 interferon, produced during viral infection influences the lymphatic network of the lymph node in mice. We found that following an interferon inducing stimulus, such as viral infection or polyI:C, programmed death ligand 1 (PD-L1) expression is dynamically upregulated on lymphatic endothelial cells (LEC). We find that reception of type 1 interferon by LECs is important for the upregulation of PD-L1 of mouse and human LECs and the inhibition of LEC expansion in the LN. Expression of PD-L1 by LECs is also important for the regulation of lymph node expansion and contraction after an interferon inducting stimulus. We demonstrate a direct role for both type 1 interferon and PD-L1 in inhibiting LEC division and in promoting LEC survival. Together these data reveal a novel mechanism for the coordination of type 1 IFN and PD-L1 in manipulating LEC expansion and survival during an inflammatory immune response.