Disruption of IL-21 Signaling Affects T Cell-B Cell Interactions and Abrogates Protective Humoral Immunity to Malaria

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. © 2015 pérez-mazliah et al.