PD-1 Dependent Exhaustion of CD8+ T Cells Drives Chronic Malaria

• Published in: Cell reports (Cambridge) 2013-12, Vol.5 (5), p.1204-1213
• Main Authors: Horne-Debets, Joshua M., Faleiro, Rebecca, Karunarathne, Deshapriya S., Liu, Xue Q., Lineburg, Katie E., Poh, Chek Meng, Grotenbreg, Gijsbert M., Hill, Geoffrey R., MacDonald, Kelli P.A., Good, Michael F., Renia, Laurent, Ahmed, Rafi, Sharpe, Arlene H., Wykes, Michelle N.
• Format: Article
• Language: English
• Subjects: Animals; CD8-Positive T-Lymphocytes - metabolism; CD8-Positive T-Lymphocytes - pathology; Malaria - blood; Malaria - immunology; Malaria - metabolism; Mice; Mice, Inbred C57BL; Programmed Cell Death 1 Receptor - genetics; Programmed Cell Death 1 Receptor - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2013.11.002

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. [Display omitted] •PD-1, per se, drives chronic malaria•CD8+ T cells protect against chronic malaria•PD-1 mediates a 95% loss of Plasmodium-specific CD8+ T cells•PD-1 mediates exhaustion of Plasmodium-specific CD8+ and CD4+ T cells Blood-stage malaria causes global morbidity and mortality. Antibodies and CD4+ T cells protect against infection. Here, Wykes and colleagues show that, in contrast to widely held views, parasite-specific CD8+ T cells control both acute and chronic blood-stage disease even when parasite-specific antibodies and CD4+ T cells are present. Critically, they show that PD-1 mediates up to a 95% reduction in numbers and functional capacity of parasite-specific CD8+ T cells that provides a molecular explanation for this chronic infection.