- 14 June 2018
1:00 pm - 2:00 pm
Thursday 14 June 2018, 1.00 PM
Auditorium, Level 6, Bancroft Building
The complexity of Programmed cell death-1 ligand 2
Dr Michelle Wykes,
QIMR Berghofer Medical Research Institute
Many pathogens, including Plasmodium spp., exploit the programmed death-1 (PD-1)/PD-1 ligand-1 (PD-L1) pathway to ‘deactivate’ T cell functions but the role of PD-1/PD-L2 remains unclear. A definitive role for PD1 in malarial pathogenesis was established when PD1-deficient mice were shown to rapidly and completely clear P. chabaudi infections, which usually cause chronic malaria. We thus studied malarial infections to understand the relative contribution of PD-L1 and PD-L2 to immunity. We found that higher PD-L2 expression on blood dendritic cells (DC), from Plasmodium falciparum-infected individuals, correlated with lower parasitemia. Mechanistic studies in mice showed that while PD-L1 expressed by DCs did indeed attenuate immune responses against malaria, PDL2 protein expressed on the same DCs improved immune responses by inhibiting PDL1–PD1 interactions. Overall, PD-L2 is indispensable for establishing effective CD4+ Th1 immunity. We have now data which shows a role for PD-L2 in the control of cancer. These studies show a new function for PD-L2, which has 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.
Michelle Wykes is Group Leader of the Molecular Immunology Laboratory at the QIMR Berghofer. She studies the mechanisms by which Plasmodium spp, which cause malaria, are able to evade immunity. Her research has predominantly focussed on understanding the role DCs play in the pathogenesis of malaria. Her group has shown how Programmed cell death-1 (PD-1) and its ligands PD-L1 and PD-L2 (both expressed on dendritic cells) drive chronic and severe malaria. Her group published a paradigm–shifting study which showed PD-L2 has a regulatory role in mediating immunity. They showed PD-L2 is crucial for establishing effective CD4+ Th1 immunity and designed a novel form of soluble PD-L2 which cures malaria and protects against re-infection, 150 days after the original infection. This line of research, published in Immunity and described in Nature Reviews Immunology, has potential to be used as a novel therapeutic for malaria, other infectious diseases, as well as cancer.