Programmed death-1 ligand 2-mediated regulation of the PD-L1 to PD-1 axis is essential for establishing CD4⁺ T cell immunity

Karunarathne, Deshapriya, Horne-Debets, Joshua M., Huang, Johnny X., Faleiro, Rebecca, Leow, Chiuan Yee, Amante, Fiona, Watkins, Thomas S., Miles, John, Dwyer, Patrick J., Stacey, Katryn J., Yarski, Michael, Poh, Chek Meng, Lee, Jason S., Cooper, Matthew A., Rénia, Laurent, Richard, Derek, McCarthy, James S., Sharpe, Arlene H., and Wykes, Michelle N. (2016) Programmed death-1 ligand 2-mediated regulation of the PD-L1 to PD-1 axis is essential for establishing CD4⁺ T cell immunity. Immunity, 45 (2). pp. 333-345.

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Abstract

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.

Item ID: 45622
Item Type: Article (Research - C1)
ISSN: 1097-4180
Funders: National Health and Medical Research Council of Australia (NHMRC), Australian Research Council (ARC), University of Queensland (UQ), National Research Foundation Singapore (NRF), National University of Singapore (NUS), National Institutes of Health (NIH)
Projects and Grants: NRF NRF2007NRF-RF001-22, NIH grant P01 AI56299
Date Deposited: 06 Sep 2016 05:33
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1107 Immunology > 110702 Applied Immunology (incl Antibody Engineering, Xenotransplantation and T-cell Therapies) @ 100%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920108 Immune System and Allergy @ 100%
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