Abstract
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.
Highlights
Robust immunity to malaria is difficult to generate in humans through natural infection or vaccination [1,2], it is clear that Plasmodium-specific antibodies offer the best known form of immunological protection against blood-stage parasites [3,4,5,6,7,8], and may control liver-infective sporozoites [9,10]
We found that cytokine-signalling via the receptor IFNAR1 delayed the production of Plasmodium-specific antibody responses
We reveal that an innate cytokine response, which occurs during blood-stage Plasmodium infection in humans, obstructs the onset of antibody–mediated immunity during experimental malaria
Summary
Robust immunity to malaria is difficult to generate in humans through natural infection or vaccination [1,2], it is clear that Plasmodium-specific antibodies offer the best known form of immunological protection against blood-stage parasites [3,4,5,6,7,8], and may control liver-infective sporozoites [9,10]. Considering that a highly effective malaria vaccine remains elusive, it is important to understand how the onset of humoral immunity to blood-stage Plasmodium parasites is controlled, and whether this process can be boosted, to accelerate or otherwise enhance antibody-mediated immunity to malaria. Non-lethal blood-stage Plasmodium infection are useful for studying humoral immunity to malaria, since mice fail to control parasitemias and display increased disease severity in the absence of parasite-specific antibodies [4,11,12,13,14]. With the exception of these reports, in vivo studies of Tfh cells and GC B-cells during experimental malaria remain sparse While these recent reports focused on molecules expressed by CD4+ T-cells themselves, less effort has been directed towards determining whether T-cell extrinsic factors, such as innate or inflammatory cytokines, can control humoral immunity
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