Date Published: November 3, 2016
Publisher: Public Library of Science
Author(s): Ismail Sebina, Kylie R. James, Megan S. F. Soon, Lily G. Fogg, Shannon E. Best, Fabian de Labastida Rivera, Marcela Montes de Oca, Fiona H. Amante, Bryce S. Thomas, Lynette Beattie, Fernando Souza-Fonseca-Guimaraes, Mark J. Smyth, Paul J. Hertzog, Geoffrey R. Hill, Andreas Hutloff, Christian R. Engwerda, Ashraful Haque, Maria M. Mota.
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.
Although robust immunity to malaria is difficult to generate in humans through natural infection or vaccination [1,2], it is nonetheless 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 also 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.
Here, using two mouse models of non-lethal blood-stage malaria, we have provided evidence that the onset of protective humoral immunity to Plasmodium can be influenced by an innate cytokine signalling pathway, in this case Type I Interferon-signalling via IFNAR1. Therefore, we have demonstrated for the first time that innate immune cytokines can limit the onset of antibody production and B-cell responses to Plasmodium. Moreover, we found that release from IFNAR1-mediated immune-regulation enhanced humoral immune responses and parasite control in a manner dependent upon ICOS-signalling.