title: Expression of PD-1/LAG-3 and cytokine production by CD4(+) T cells during infection with Plasmodium parasites.
abstract: CD4(+) T cells play critical roles in protection against the blood stage of malarial infection; however, their uncontrolled activation can be harmful to the host. In this study, in which rodent models of Plasmodium parasites were used, the expression of inhibitory receptors on activated CD4(+) T cells and their cytokine production was compared with their expression in a bacterial and another protozoan infection. CD4(+) T cells from mice infected with P. yoelii 17XL, P yoelii 17XNL, P. chabaudi, P. vinckei and P. berghei expressed the inhibitory receptors, PD-1 and LAG-3, as early as 6 days after infection, whereas those from either Listeria monocytogenes- or Leishmania major-infected mice did not. In response to T-cell receptor stimulation, CD4(+) T cells from mice infected with all the pathogens under study produced high concentrations of IFN-γ. IL-2 production was reduced in mice infected with Plasmodium species, but not in those infected with Listeria or Leishmania. In vitro blockade of the interaction between PD-1 and its ligands resulted in increased IFN-γ production in response to Plasmodium antigens, implying that PD-1 expressed on activated CD4(+) T cells actively inhibits T cell immune responses. Studies using Myd88(-/-), Trif(-/-) and Irf3(-/-) mice showed that induction of these CD4(+) T cells and their ability to produce cytokines is largely independent of TLR signaling. These studies suggest that expression of the inhibitory receptors PD-1 and LAG-3 on CD4(+) T cells and their reduced IL-2 production are common characteristic features of Plasmodium infection.
authors.affiliation: Division of Immunology, Department of Molecular Microbiology and Immunology, Graduate School of Biomedical Sciences, Nagasaki University, 1-12-4, Sakamoto, Nagasaki 852-8523, Japan.
authors.forename: Henrietta T
authors.initials: HT
authors.lastname: Doe
authors.affiliation: Division of Immunology, Department of Molecular Microbiology and Immunology, Graduate School of Biomedical Sciences, Nagasaki University, 1-12-4, Sakamoto, Nagasaki 852-8523, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kimura
authors.affiliation: Division of Immunology, Department of Molecular Microbiology and Immunology, Graduate School of Biomedical Sciences, Nagasaki University, 1-12-4, Sakamoto, Nagasaki 852-8523, Japan.
authors.forename: Mana
authors.initials: M
authors.lastname: Miyakoda
authors.affiliation: Division of Immunology, Department of Molecular Microbiology and Immunology, Graduate School of Biomedical Sciences, Nagasaki University, 1-12-4, Sakamoto, Nagasaki 852-8523, Japan.
authors.forename: Kazumi
authors.initials: K
authors.lastname: Kimura
authors.affiliation: Division of Immunology, Department of Molecular Microbiology and Immunology, Graduate School of Biomedical Sciences, Nagasaki University, 1-12-4, Sakamoto, Nagasaki 852-8523, Japan.
authors.forename: Masoud
authors.initials: M
authors.lastname: Akbari
authors.affiliation: Division of Immunology, Department of Molecular Microbiology and Immunology, Graduate School of Biomedical Sciences, Nagasaki University, 1-12-4, Sakamoto, Nagasaki 852-8523, Japan.
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Yui
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D015703:Antigens, CD / Q000096:biosynthesis* / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis* / Q000276:immunology; D007376:Interleukin-2 / Q000096:biosynthesis / Q000276:immunology; D018320:Leishmania major / Q000276:immunology; D016773:Leishmaniasis, Cutaneous / Q000276:immunology / Q000469:parasitology; D008089:Listeria monocytogenes / Q000276:immunology; D008088:Listeriosis / Q000276:immunology; D008213:Lymphocyte Activation; D008288:Malaria / Q000276:immunology* / Q000469:parasitology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010961:Plasmodium / Q000276:immunology*; D061026:Programmed Cell Death 1 Receptor / Q000096:biosynthesis* / Q000276:immunology; D000093322:Lymphocyte Activation Gene 3 Protein
chemical_list: D015703:Antigens, CD; D016207:Cytokines; D007376:Interleukin-2; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D000093322:Lymphocyte Activation Gene 3 Protein
keywords: CD4+ T cells; cytokines; inhibitory receptor; malaria