title: Disruption of IL-21 signaling affects T cell-B cell interactions and abrogates protective humoral immunity to malaria.
abstract: Interleukin-21 signaling is important for germinal center B-cell responses, isotype switching and generation of memory B cells. However, a role for IL-21 in antibody-mediated protection against pathogens has not been demonstrated. Here we show that IL-21 is produced by T follicular helper cells and co-expressed with IFN-γ during an erythrocytic-stage malaria infection of Plasmodium chabaudi in mice. Mice deficient either in IL-21 or the IL-21 receptor fail to resolve the chronic phase of P. chabaudi infection and P. yoelii infection resulting in sustained high parasitemias, and are not immune to re-infection. This is associated with abrogated P. chabaudi-specific IgG responses, including memory B cells. Mixed bone marrow chimeric mice, with T cells carrying a targeted disruption of the Il21 gene, or B cells with a targeted disruption of the Il21r gene, demonstrate that IL-21 from T cells signaling through the IL-21 receptor on B cells is necessary to control chronic P. chabaudi infection. Our data uncover a mechanism by which CD4+ T cells and B cells control parasitemia during chronic erythrocytic-stage malaria through a single gene, Il21, and demonstrate the importance of this cytokine in the control of pathogens by humoral immune responses. These data are highly pertinent for designing malaria vaccines requiring long-lasting protective B-cell responses.
authors.affiliation: Division of Parasitology, MRC National Institute for Medical Research (NIMR), London, United Kingdom.
authors.forename: Damián
authors.initials: D
authors.lastname: Pérez-Mazliah
authors.affiliation: Division of Parasitology, MRC National Institute for Medical Research (NIMR), London, United Kingdom.
authors.forename: Dorothy Hui Lin
authors.initials: DH
authors.lastname: Ng
authors.affiliation: Division of Parasitology, MRC National Institute for Medical Research (NIMR), London, United Kingdom.
authors.forename: Ana Paula
authors.initials: AP
authors.lastname: Freitas do Rosário
authors.affiliation: Division of Parasitology, MRC National Institute for Medical Research (NIMR), London, United Kingdom.
authors.forename: Sarah
authors.initials: S
authors.lastname: McLaughlin
authors.affiliation: Division of Parasitology, MRC National Institute for Medical Research (NIMR), London, United Kingdom.
authors.forename: Béatris
authors.initials: B
authors.lastname: Mastelic-Gavillet
authors.affiliation: Division of Parasitology, MRC National Institute for Medical Research (NIMR), London, United Kingdom.
authors.forename: Jan
authors.initials: J
authors.lastname: Sodenkamp
authors.affiliation: Division of Parasitology, MRC National Institute for Medical Research (NIMR), London, United Kingdom.
authors.forename: Garikai
authors.initials: G
authors.lastname: Kushinga
authors.affiliation: Division of Parasitology, MRC National Institute for Medical Research (NIMR), London, United Kingdom.
authors.forename: Jean
authors.initials: J
authors.lastname: Langhorne
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D002450:Cell Communication / Q000276:immunology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D056724:Immunity, Humoral / Q000276:immunology*; D007378:Interleukins / Q000276:immunology*; D008288:Malaria / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016788:Plasmodium chabaudi / Q000276:immunology; D010967:Plasmodium yoelii / Q000276:immunology; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*; D000098546:Interleukin-21
chemical_list: D007378:Interleukins; D000098546:Interleukin-21