title: Programmed Death-1 Ligand 2-Mediated Regulation of the PD-L1 to PD-1 Axis Is Essential for Establishing CD4(+) T Cell Immunity.
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.
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane City, QLD 4029, Australia.
authors.forename: Deshapriya S
authors.initials: DS
authors.lastname: Karunarathne
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane City, QLD 4029, Australia.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Horne-Debets
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD 4072, Australia.
authors.forename: Johnny X
authors.initials: JX
authors.lastname: Huang
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane City, QLD 4029, Australia.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Faleiro
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane City, QLD 4029, Australia.
authors.forename: Chiuan Yee
authors.initials: CY
authors.lastname: Leow
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane City, QLD 4029, Australia.
authors.forename: Fiona
authors.initials: F
authors.lastname: Amante
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane City, QLD 4029, Australia.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Watkins
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane City, QLD 4029, Australia.
authors.forename: John J
authors.initials: JJ
authors.lastname: Miles
authors.affiliation: Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane 4059, Australia.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Dwyer
authors.affiliation: School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, Australia.
authors.forename: Katryn J
authors.initials: KJ
authors.lastname: Stacey
authors.affiliation: Millennium Science, 4 Miles Street, Mulgrave, VIC 3170, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Yarski
authors.affiliation: Singapore Immunology Network, A(∗)STAR, Singapore 136648, Singapore; Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore 117597, Singapore.
authors.forename: Chek Meng
authors.initials: CM
authors.lastname: Poh
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane City, QLD 4029, Australia.
authors.forename: Jason S
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD 4072, Australia.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Cooper
authors.affiliation: Singapore Immunology Network, A(∗)STAR, Singapore 136648, Singapore; Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore 117597, Singapore.
authors.forename: Laurent
authors.initials: L
authors.lastname: Rénia
authors.affiliation: School of Biomedical Research, Queensland University of Technology, Brisbane, QLD 4102, Australia.
authors.forename: Derek
authors.initials: D
authors.lastname: Richard
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane City, QLD 4029, Australia.
authors.forename: James S
authors.initials: JS
authors.lastname: McCarthy
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Arlene H
authors.initials: AH
authors.lastname: Sharpe
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane City, QLD 4029, Australia. Electronic address: michelle.wykes@qimrberghofer.edu.au.
authors.forename: Michelle N
authors.initials: MN
authors.lastname: Wykes
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives / Q000627:therapeutic use; D000328:Adult; D000818:Animals; D000962:Antimalarials / Q000627:therapeutic use; D060890:B7-H1 Antigen / Q000235:genetics / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D002986:Clinical Trials as Topic; D003713:Dendritic Cells / Q000276:immunology* / Q000469:parasitology; D005260:Female; D006801:Humans; D007111:Immunity, Cellular; D008213:Lymphocyte Activation; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D018512:Parasitemia / Q000276:immunology; D010545:Peroxides / Q000627:therapeutic use; D010963:Plasmodium falciparum / Q000276:immunology*; D061027:Programmed Cell Death 1 Ligand 2 Protein / Q000235:genetics / Q000378:metabolism*; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000627:therapeutic use; D014230:Triazoles / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D000962:Antimalarials; D060890:B7-H1 Antigen; C105992:PDCD1 protein, human; C556978:Pdcd1lg2 protein, mouse; D010545:Peroxides; D061027:Programmed Cell Death 1 Ligand 2 Protein; D061026:Programmed Cell Death 1 Receptor; D011743:Pyrimidines; D014230:Triazoles; C000606979:DSM265; D000218:Adamantane; C558165:artefenomel