title: Therapeutic blockade of PD-L1 and LAG-3 rapidly clears established blood-stage Plasmodium infection.
abstract: Infection of erythrocytes with Plasmodium species induces clinical malaria. Parasite-specific CD4(+) T cells correlate with lower parasite burdens and severity of human malaria and are needed to control blood-stage infection in mice. However, the characteristics of CD4(+) T cells that determine protection or parasite persistence remain unknown. Here we show that infection of humans with Plasmodium falciparum resulted in higher expression of the inhibitory receptor PD-1 associated with T cell dysfunction. In vivo blockade of the PD-1 ligand PD-L1 and the inhibitory receptor LAG-3 restored CD4(+) T cell function, amplified the number of follicular helper T cells and germinal-center B cells and plasmablasts, enhanced protective antibodies and rapidly cleared blood-stage malaria in mice. Thus, chronic malaria drives specific T cell dysfunction, and proper function can be restored by inhibitory therapies to enhance parasite control.
authors.affiliation: Department of Microbiology, University of Iowa, Iowa City, Iowa, USA.
authors.forename: Noah S
authors.initials: NS
authors.lastname: Butler
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Moebius
authors.forename: Lecia L
authors.initials: LL
authors.lastname: Pewe
authors.forename: Boubacar
authors.initials: B
authors.lastname: Traore
authors.forename: Ogobara K
authors.initials: OK
authors.lastname: Doumbo
authors.forename: Lorraine T
authors.initials: LT
authors.lastname: Tygrett
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Waldschmidt
authors.forename: Peter D
authors.initials: PD
authors.lastname: Crompton
authors.forename: John T
authors.initials: JT
authors.lastname: Harty
mesh_terms: D000208:Acute Disease; D000818:Animals; D015703:Antigens, CD / Q000187:drug effects* / Q000276:immunology; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000469:parasitology; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors* / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000469:parasitology; D002648:Child; D002675:Child, Preschool; D002908:Chronic Disease; D004912:Erythrocytes / Q000276:immunology / Q000469:parasitology; D005260:Female; D018858:Germinal Center / Q000187:drug effects / Q000276:immunology / Q000469:parasitology; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000276:immunology; D008302:Mali; D051379:Mice; D008810:Mice, Inbred C57BL; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000276:immunology; D014481:United States; D015854:Up-Regulation / Q000187:drug effects; D000093322:Lymphocyte Activation Gene 3 Protein
chemical_list: D015703:Antigens, CD; D060890:B7-H1 Antigen; C423236:CD274 protein, human; C498919:Cd274 protein, mouse; D000093322:Lymphocyte Activation Gene 3 Protein