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

Ismail Sebina, Kylie R James, Megan S F Soon, Lily G. Fogg, Shannon E Best, Fabian Rivera 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 K M Nazmul Haque

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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.

Original languageEnglish
Article numbere1005999
JournalPLoS Pathogens
Volume12
Issue number11
DOIs
Publication statusPublished - 1 Nov 2016
Externally publishedYes

Cite this

Sebina, I., James, K. R., Soon, M. S. F., Fogg, L. G., Best, S. E., de Labastida Rivera, F. R., ... Haque, A. K. M. N. (2016). IFNAR1-Signalling Obstructs ICOS-mediated Humoral Immunity during Non-lethal Blood-Stage Plasmodium Infection. PLoS Pathogens, 12(11), [e1005999]. https://doi.org/10.1371/journal.ppat.1005999
Sebina, Ismail ; James, Kylie R ; Soon, Megan S F ; Fogg, Lily G. ; Best, Shannon E ; de Labastida Rivera, Fabian Rivera ; Montes de Oca, Marcela ; Amante, Fiona H ; Thomas, Bryce S. ; Beattie, Lynette ; Souza-Fonseca-Guimaraes, Fernando ; Smyth, Mark J ; Hertzog, Paul J. ; Hill, Geoffrey R ; Hutloff, Andreas ; Engwerda, Christian R ; Haque, Ashraful K M Nazmul. / IFNAR1-Signalling Obstructs ICOS-mediated Humoral Immunity during Non-lethal Blood-Stage Plasmodium Infection. In: PLoS Pathogens. 2016 ; Vol. 12, No. 11.
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title = "IFNAR1-Signalling Obstructs ICOS-mediated Humoral Immunity during Non-lethal Blood-Stage Plasmodium Infection",
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.",
author = "Ismail Sebina and James, {Kylie R} and Soon, {Megan S F} and Fogg, {Lily G.} and Best, {Shannon E} and {de Labastida Rivera}, {Fabian Rivera} and {Montes de Oca}, Marcela and Amante, {Fiona H} and Thomas, {Bryce S.} and Lynette Beattie and Fernando Souza-Fonseca-Guimaraes and Smyth, {Mark J} and Hertzog, {Paul J.} and Hill, {Geoffrey R} and Andreas Hutloff and Engwerda, {Christian R} and Haque, {Ashraful K M Nazmul}",
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Sebina, I, James, KR, Soon, MSF, Fogg, LG, Best, SE, de Labastida Rivera, FR, Montes de Oca, M, Amante, FH, Thomas, BS, Beattie, L, Souza-Fonseca-Guimaraes, F, Smyth, MJ, Hertzog, PJ, Hill, GR, Hutloff, A, Engwerda, CR & Haque, AKMN 2016, 'IFNAR1-Signalling Obstructs ICOS-mediated Humoral Immunity during Non-lethal Blood-Stage Plasmodium Infection', PLoS Pathogens, vol. 12, no. 11, e1005999. https://doi.org/10.1371/journal.ppat.1005999

IFNAR1-Signalling Obstructs ICOS-mediated Humoral Immunity during Non-lethal Blood-Stage Plasmodium Infection. / Sebina, Ismail; James, Kylie R; Soon, Megan S F; Fogg, Lily G.; Best, Shannon E; de Labastida Rivera, Fabian Rivera; Montes de Oca, Marcela; Amante, Fiona H; Thomas, Bryce S.; Beattie, Lynette; Souza-Fonseca-Guimaraes, Fernando; Smyth, Mark J; Hertzog, Paul J.; Hill, Geoffrey R; Hutloff, Andreas; Engwerda, Christian R; Haque, Ashraful K M Nazmul.

In: PLoS Pathogens, Vol. 12, No. 11, e1005999, 01.11.2016.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - IFNAR1-Signalling Obstructs ICOS-mediated Humoral Immunity during Non-lethal Blood-Stage Plasmodium Infection

AU - Sebina, Ismail

AU - James, Kylie R

AU - Soon, Megan S F

AU - Fogg, Lily G.

AU - Best, Shannon E

AU - de Labastida Rivera, Fabian Rivera

AU - Montes de Oca, Marcela

AU - Amante, Fiona H

AU - Thomas, Bryce S.

AU - Beattie, Lynette

AU - Souza-Fonseca-Guimaraes, Fernando

AU - Smyth, Mark J

AU - Hertzog, Paul J.

AU - Hill, Geoffrey R

AU - Hutloff, Andreas

AU - Engwerda, Christian R

AU - Haque, Ashraful K M Nazmul

PY - 2016/11/1

Y1 - 2016/11/1

N2 - 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.

AB - 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.

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