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

Ismail Sebina, Kylie R James (Corresponding Author), Megan Soon (Corresponding Author), Lily G Fogg (Corresponding Author), Shannon E Best (Corresponding Author), Fabian de Labastida Rivera (Corresponding Author), Marcela Montes de Oca (Corresponding Author), Fiona Amante (Corresponding Author), Bryce Thomas (Corresponding Author), Lynette Beattie (Corresponding Author), Fernando Souza-Fonsec-Guimaraes (Corresponding Author), Mark J Smyth (Corresponding Author), Paul J Hertzog (Corresponding Author), Geoffrey R Hill (Corresponding Author), Andreas Hutloff (Corresponding Author), Christian R Engwerda (Corresponding Author), Ashraful Haque (Corresponding Author)

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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.
Original languageEnglish
Article numbere1005999
JournalPLoS Pathogens
Issue number11
Publication statusPublished - 3 Nov 2016


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