title: Induction of Inhibitory Receptors on T Cells During Plasmodium vivax Malaria Impairs Cytokine Production.
abstract: The function and regulation of the immune response triggered during malaria is complex and poorly understood, and there is a particular paucity of studies conducted in humans infected with Plasmodium vivax. While it has been proposed that T-cell-effector responses are crucial for protection against blood-stage malaria in mice, the mechanisms behind this in humans remain poorly understood. Experimental models of malaria have shown that the regulatory molecules, cytotoxic T-lymphocyte attenuator-4 (CTLA-4), lymphocyte activation gene-3 (LAG-3), and programmed death-1 (PD-1) are involved in the functional impairment of T cells during infection. Our goal was to define the role of these molecules during P. vivax malaria. We demonstrate that infection triggers the expression of regulatory molecules on T cells. The pattern of expression differs in CD4(+) and CD8(+) T cells. Higher frequencies of CD4(+) express more than 1 regulatory molecule compared to CD8(+) T cells. Moreover, lower proportions of CD4(+) T cells coexpress regulatory molecules, but are still able to proliferate. Importantly, simultaneously blockade of the CLTA-4, PD-1, and T-cell immunoglobulin and mucin-3 signaling restores the cytokine production by antigen-specific cells. These data support the hypothesis that upregulation of inhibitory receptors on T cells during P. vivax malaria impairs parasite-specific T-cell effector function.
authors.affiliation: Laboratório de Immunopatologia, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais.
authors.forename: Pedro A C
authors.initials: PA
authors.lastname: Costa
authors.affiliation: Laboratório de Immunopatologia, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais.
authors.forename: Fabiana M S
authors.initials: FM
authors.lastname: Leoratti
authors.affiliation: Laboratório de Immunopatologia, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais.
authors.forename: Maria M
authors.initials: MM
authors.lastname: Figueiredo
authors.affiliation: Centro de Pesquisas em Medicina Tropical de Rondônia, Porto Velho.
authors.forename: Mauro S
authors.initials: MS
authors.lastname: Tada
authors.affiliation: Centro de Pesquisas em Medicina Tropical de Rondônia, Porto Velho.
authors.forename: Dhelio B
authors.initials: DB
authors.lastname: Pereira
authors.affiliation: Laboratório de Immunopatologia, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais.
authors.forename: Caroline
authors.initials: C
authors.lastname: Junqueira
authors.affiliation: Departamento de Análises Clínicas e Toxicológicas, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, Brazil.
authors.forename: Irene S
authors.initials: IS
authors.lastname: Soares
authors.affiliation: T Lymphocyte Biology Unit, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Barber
authors.affiliation: Laboratório de Immunopatologia, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais Departamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Ricardo T
authors.initials: RT
authors.lastname: Gazzinelli
authors.affiliation: Laboratório de Immunopatologia, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais.
authors.forename: Lis R V
authors.initials: LR
authors.lastname: Antonelli
mesh_terms: D000328:Adult; D016207:Cytokines / Q000037:antagonists & inhibitors*; D005260:Female; D054884:Host-Pathogen Interactions; D006801:Humans; D007108:Immune Tolerance; D016780:Malaria, Vivax / Q000276:immunology* / Q000469:parasitology; D008297:Male; D008875:Middle Aged; D010966:Plasmodium vivax / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology*; D055815:Young Adult
chemical_list: D016207:Cytokines; D011948:Receptors, Antigen, T-Cell
keywords: Plasmodium vivax; T cells; malaria; regulatory molecules