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.

cGAS-mediated control of blood-stage malaria promotes Plasmodium-specific germinal center responses

“…As reported for the nonantigen-specific CD4 + T cell response in P. chabaudi (34) Figure 3B). Furthermore, we observed no differences in the intracellular expression of the Th1 master transcription factor Tbet on GP 66 :I-A b+ CD4…”

Evaluating antidisease immunity to malaria and implications for vaccine design

“…directly targeted at reducing parasite burden). Indeed, processes that ablate humoral responses have been associated with high parasitaemia in murine malaria models, further confirming the necessity of antibody responses 44. Similarly, multiple longitudinal reports, such as the Garki project45 and others,46, 47, 48 have also associated high antibody levels with reduced incidence of clinical symptoms.…”

Development of a Novel CD4+ TCR Transgenic Line That Reveals a Dominant Role for CD8+ Dendritic Cells and CD40 Signaling in the Generation of Helper and CTL Responses to Blood-Stage Malaria

“…IL-2-, IL-4-, and IFN-g-deficient mice experience more exacerbated relapses of parasitemia than do WT mice, but are eventually able to control the infection (86,87). However, IL-21 KO mice are unable to control P. chabaudi parasitemia (88). Not surprisingly, the absence of CD8 + DC in this infection results in impaired parasite control and more pronounced relapses (40).…”