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

PLoS Pathogens

Christian R. Engwerda¹  Ashraful Haque²  Andreas Hutloff³  Geoffrey R. Hill⁴  Paul J. Hertzog⁴  Fiona H. Amante⁵  Bryce S. Thomas⁵  Mark J. Smyth⁵  Lynette Beattie⁵  Megan S. F. Soon⁶  Shannon E. Best⁶  Fernando Souza-Fonseca-Guimaraes⁶  Marcela Montes de Oca⁶  Fabian de Labastida Rivera⁶  Ismail Sebina⁶  Lily G. Fogg⁷  Kylie R. James⁷ 

[1] Bone Marrow Transplantation Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia;Chronic Immune Reactions, German Rheumatism Research Centre (DRFZ), a Leibniz Institute, Berlin, Germany;Hudson Institute of Medical Research, Clayton, Victoria, Australia;Immunity in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute Herston, Queensland, Australia;Immunology and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia;Malaria Immunology Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia;The University of Queensland, School of Medicine PhD Program, Herston, Queensland, Australia

关键词: Parasitic diseases;    T cells;    B cells;    Malaria;    Malarial parasites;    Immune response;    Humoral immune response;    Humoral immunity;   

DOI  :  10.1371/journal.ppat.1005999

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY