Programmed Death-1 Ligand 2-Mediated Regulation of the PD-L1 to PD-1 Axis Is Essential for Establishing CD4+ T Cell Immunity

Deshapriya S. Karunarathne, Joshua M. Horne-Debets, Johnny X. Huang, Rebecca Faleiro, Chiuan Yee Leow, Fiona Amante, Thomas S. Watkins, John J. Miles, Patrick J. Dwyer, Katryn J. Stacey, Michael Yarski, Chek Meng Poh, Jason S. Lee, Matthew A. Cooper, Laurent Rénia, Derek Richard, James S. McCarthy, Arlene H. Sharpe, Michelle N. Wykes

Many pathogens, including Plasmodium spp., 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.