Many pathogens, including Plasmodiumspp., exploit the interaction of programmed death-1 (PD-1) with PD-1-ligand-1 (PD-L1) to "deactivate'' T cell functions, but the role of PD-L2 remains unclear. We studied malarial infections to understand the contribution of PD-L2 to immunity. Here we have shown that higher PD-L2 expression on blood dendritic cells, from Plasmodium falciparum-infected individuals, correlated with lower parasitemia. Mechanistic studies in mice showed that PD-L2 was indispensable for establishing effective CD4(+) T cell immunity against malaria, because it not only inhibited PD-L1 to PD-1 activity but also increased CD3 and inducible co-stimulator (ICOS) expression on T cells. Importantly, administration of soluble multimeric PD-L2 to mice with lethal malaria was sufficient to dramatically improve immunity and survival. These studies show immuno-regulation by PD-L2, which has the potential to be translated into an effective treatment for malaria and other diseases where T cell immunity is ineffective or short-lived due to PD-1-mediated signaling.
|Authors||Karunarathne, Deshapriya S.; Horne-Debets, Joshua M.; Huang, Johnny X.; Faleiro, Rebecca; Leow, Chiuan Yee; Amante, Fiona; Watkins, Thomas S.; Miles, John J.; Dwyer, Patrick J.; Stacey, Katryn J.; Yarski, Michael; Poh, Chek Meng; Lee, Jason S.; Cooper, Matthew A.; Renia, Laurent; Richard, Derek; McCarthy, James S.; Sharpe, Arlene H.; Wykes, Michelle N.|
|Funding Body||NHMRC (Australia)|