title: PD-1 dependent exhaustion of CD8+ T cells drives chronic malaria.
abstract: Malaria is a highly prevalent disease caused by infection by Plasmodium spp., which infect hepatocytes and erythrocytes. Blood-stage infections cause devastating symptoms and can persist for years. Antibodies and CD4(+) T cells are thought to protect against blood-stage infections. However, there has been considerable difficulty in developing an efficacious malaria vaccine, highlighting our incomplete understanding of immunity against this disease. Here, we used an experimental rodent malaria model to show that PD-1 mediates up to a 95% reduction in numbers and functional capacity of parasite-specific CD8(+) T cells. Furthermore, in contrast to widely held views, parasite-specific CD8(+) T cells are required to control both acute and chronic blood-stage disease even when parasite-specific antibodies and CD4(+) T cells are present. Our findings provide a molecular explanation for chronic malaria that will be relevant to future malaria-vaccine design and may need consideration when vaccine development for other infections is problematic.
authors: QIMR Berghofer Medical Research Institute, 300 Herston Road, Brisbane, QLD 4029, Australia.
authors: Joshua M
authors: JM
authors: Horne-Debets
authors: QIMR Berghofer Medical Research Institute, 300 Herston Road, Brisbane, QLD 4029, Australia.
authors: Rebecca
authors: R
authors: Faleiro
authors: QIMR Berghofer Medical Research Institute, 300 Herston Road, Brisbane, QLD 4029, Australia.
authors: Deshapriya S
authors: DS
authors: Karunarathne
authors: QIMR Berghofer Medical Research Institute, 300 Herston Road, Brisbane, QLD 4029, Australia; Institute for Glycomics, Griffith University, Gold Coast Campus, QLD 4222, Australia.
authors: Xue Q
authors: XQ
authors: Liu
authors: QIMR Berghofer Medical Research Institute, 300 Herston Road, Brisbane, QLD 4029, Australia.
authors: Katie E
authors: KE
authors: Lineburg
authors: Singapore Immunology Network, Agency for Science, Technology and Research (A(∗)STAR), Singapore 136648, Singapore; Department of Microbiology, Life Sciences Institute, National University of Singapore, Singapore 117597, Singapore.
authors: Chek Meng
authors: CM
authors: Poh
authors: Department of Microbiology, Life Sciences Institute, National University of Singapore, Singapore 117597, Singapore; Department of Biological Sciences, Faculty of Science, Life Sciences Institute, National University of Singapore, Singapore, Singapore 117597, Singapore; Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore 117597, Singapore.
authors: Gijsbert M
authors: GM
authors: Grotenbreg
authors: QIMR Berghofer Medical Research Institute, 300 Herston Road, Brisbane, QLD 4029, Australia.
authors: Geoffrey R
authors: GR
authors: Hill
authors: QIMR Berghofer Medical Research Institute, 300 Herston Road, Brisbane, QLD 4029, Australia.
authors: Kelli P A
authors: KP
authors: MacDonald
authors: QIMR Berghofer Medical Research Institute, 300 Herston Road, Brisbane, QLD 4029, Australia; Institute for Glycomics, Griffith University, Gold Coast Campus, QLD 4222, Australia.
authors: Michael F
authors: MF
authors: Good
authors: Singapore Immunology Network, Agency for Science, Technology and Research (A(∗)STAR), Singapore 136648, Singapore; Department of Microbiology, Life Sciences Institute, National University of Singapore, Singapore 117597, Singapore.
authors: Laurent
authors: L
authors: Renia
authors: Emory Vaccine Center, 954 Gatewood Road, Atlanta, GA 30329, USA.
authors: Rafi
authors: R
authors: Ahmed
authors: Harvard Medical School, Department of Microbiology and Immunobiology, Boston, MA 02115, USA.
authors: Arlene H
authors: AH
authors: Sharpe
authors: QIMR Berghofer Medical Research Institute, 300 Herston Road, Brisbane, QLD 4029, Australia. Electronic address: michelle.wykes@qimrberghofer.edu.au.
authors: Michelle N
authors: MN
authors: Wykes
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D008288:Malaria / Q000097:blood* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000378:metabolism*
chemical_list: D061026:Programmed Cell Death 1 Receptor