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.
Highlights
Malaria is the leading parasitic cause of morbidity and mortality worldwide; about half of the world's population is at risk of infection [1]
IL-21 signaling is essential to control the chronic phase of blood stage P. chabaudi infection
IL-21 mRNA was detected over basal naïve levels as early as 2 days post-P. chabaudi infection, there was a striking increase in the spleen by day 7 post-infection, when IL-21 mRNA levels were approximately 130-fold higher than the basal level
Summary
Malaria is the leading parasitic cause of morbidity and mortality worldwide; about half of the world's population is at risk of infection [1]. Immunity to the erythrocytic stages of malaria is thought to be primarily dependent on an antibody response. In endemic areas of Plasmodium falciparum transmission, there are associations between Plasmodium-specific antibody responses and protection against infection [2,3,4,5]. Elimination of the erythrocytic-stages of Plasmodium falciparum in infected children can be achieved by passive transfer of immune serum [2, 6], and studies in experimental models show that B cells and antibodies are important for elimination of chronic infections, and immunity to re-infection [7, 8]. A better understanding of the signals underlying activation of protective, long lasting, B-cell responses would be of great value in malaria vaccine development
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