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Immunity. 2016 Aug 16;45(2):333-45. doi: 10.1016/j.immuni.2016.07.017.

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

Author information

1
QIMR Berghofer Medical Research Institute, Brisbane City, QLD 4029, Australia.
2
Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD 4072, Australia.
3
Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane 4059, Australia.
4
School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, Australia.
5
Millennium Science, 4 Miles Street, Mulgrave, VIC 3170, Australia.
6
Singapore Immunology Network, A(∗)STAR, Singapore 136648, Singapore; Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore 117597, Singapore.
7
School of Biomedical Research, Queensland University of Technology, Brisbane, QLD 4102, Australia.
8
Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
9
QIMR Berghofer Medical Research Institute, Brisbane City, QLD 4029, Australia. Electronic address: michelle.wykes@qimrberghofer.edu.au.

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.

PMID:
27533014
DOI:
10.1016/j.immuni.2016.07.017
[Indexed for MEDLINE]
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