IFNAR1-Signalling Obstructs ICOS-mediated Humoral Immunity during Non-lethal Blood-Stage Plasmodium Infection

Parasite-specific antibodies protect against blood-stage plasmodium infection. however,in malaria-endemic regions,it takes many months for naturally-exposed individuals to develop robust humoral immunity. explanations for this have focused on antigenic variation by plasmodium,but have considered less whether host production of parasite-specific antibody is sub-optimal. in particular,it is unclear whether host immune factors might limit antibody responses. here,we explored the effect of type i interferon signalling via ifnar1 on cd4+ t-cell and b-cell responses in two non-lethal murine models of malaria,p. chabaudi chabaudi as (pcas) and p. yoelii 17xnl (py17xnl) infection. firstly,we demonstrated that cd4+ t-cells and icos-signalling were crucial for generating germinal centre (gc) b-cells,plasmablasts and parasite-specific antibodies,and likewise that t follicular helper (tfh) cell responses relied on b cells. next,we found that ifnar1-signalling impeded the resolution of non-lethal blood-stage infection,which was associated with impaired production of parasite-specific igm and several igg sub-classes. consistent with this,gc b-cell formation,ig-class switching,plasmablast and tfh differentiation were all impaired by ifnar1-signalling. ifnar1-signalling proceeded via conventional dendritic cells,and acted early by limiting activation,proliferation and icos expression by cd4+ t-cells,by restricting the localization of activated cd4+ t-cells adjacent to and within b-cell areas of the spleen,and by simultaneously suppressing th1 and tfh responses. finally,ifnar1-deficiency accelerated humoral immune responses and parasite control by boosting icos-signalling. thus,we provide evidence of a host innate cytokine response that impedes the onset of humoral immunity during experimental malaria. © 2016 sebina et al.