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.
Malaria Immunology Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.|The University of Queensland, School of Medicine PhD Program, Herston, Queensland, Australia.
Ismail
I
Sebina
Malaria Immunology Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.|The University of Queensland, School of Medicine PhD Program, Herston, Queensland, Australia.
Kylie R
KR
James
Malaria Immunology Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
Megan S F
MS
Soon
Malaria Immunology Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
Lily G
http://orcid.org/0000-0002-7489-820X
LG
Fogg
Malaria Immunology Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
Shannon E
SE
Best
Immunology and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
Fabian de
http://orcid.org/0000-0001-5241-2339
F
Labastida Rivera
Immunology and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
Marcela
M
Montes de Oca
Immunology and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
Fiona H
FH
Amante
Malaria Immunology Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
Bryce S
BS
Thomas
Immunology and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
Lynette
L
Beattie
Immunity in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute Herston, Queensland, Australia.
Fernando
F
Souza-Fonseca-Guimaraes
Immunity in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute Herston, Queensland, Australia.
Mark J
MJ
Smyth
Hudson Institute of Medical Research, Clayton, Victoria, Australia.
Paul J
PJ
Hertzog
Bone Marrow Transplantation Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
Geoffrey R
GR
Hill
Chronic Immune Reactions, German Rheumatism Research Centre (DRFZ), a Leibniz Institute, Berlin, Germany.
Andreas
http://orcid.org/0000-0002-0572-8151
A
Hutloff
Immunology and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
Christian R
CR
Engwerda
Malaria Immunology Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
Ashraful
http://orcid.org/0000-0003-2260-0026
A
Haque
D000818:Animals; D000913:Antibodies, Protozoan / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D056724:Immunity, Humoral / Q000276:immunology*; D060889:Inducible T-Cell Co-Stimulator Protein / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D008288:Malaria / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D016788:Plasmodium chabaudi / Q000276:immunology; D010967:Plasmodium yoelii / Q000276:immunology; D053633:Receptor, Interferon alpha-beta / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology
D000913:Antibodies, Protozoan; D060889:Inducible T-Cell Co-Stimulator Protein; D053633:Receptor, Interferon alpha-beta