Adults with Plasmodium falciparum malaria have higher magnitude and quality of circulating T-follicular helper cells compared to children

Damian A. Oyong; Jessica R. Loughland; Megan S.F. Soon; Jo Anne Chan; Dean Andrew; Bruce D. Wines; P. Mark Hogarth; Stuart D. Olver; Alika D. Collinge; Antiopi Varelias; James G. Beeson; Enny Kenangalem; Ric N. Price; Nicholas M. Anstey; Gabriela Minigo; Michelle J. Boyle

doi:10.1016/j.ebiom.2021.103784

Adults with Plasmodium falciparum malaria have higher magnitude and quality of circulating T-follicular helper cells compared to children

Damian A. Oyong, Jessica R. Loughland, Megan S.F. Soon, Jo Anne Chan, Dean Andrew, Bruce D. Wines, P. Mark Hogarth, Stuart D. Olver, Alika D. Collinge, Antiopi Varelias, James G. Beeson, Enny Kenangalem, Ric N. Price, Nicholas M. Anstey, Gabriela Minigo, Michelle J. Boyle

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Abstract

Background: Protective malarial antibodies are acquired more rapidly in adults than children, independently of cumulative exposure, however the cellular responses mediating these differences are unknown. CD4 T-follicular helper (Tfh) cells have key roles in inducing antibodies, with Th2-Tfh cell activation associated with antibody development in malaria. Whether Tfh cell activation in malaria is age dependent is unknown and no studies have compared Tfh cell activation in children and adults with malaria.

Methods: We undertook a comprehensive study of Tfh cells, along with B cells and antibody induction in children and adults with malaria. Activation and proliferation of circulating Tfh (cTfh) cell subsets was measured ex vivo and parasite-specific Tfh cell frequencies and functions studied with Activation Induced Marker (AIM) assays and intracellular cytokine staining.

Findings: During acute malaria, the magnitude of cTfh cell activation was higher in adults than in children and occurred across all cTfh cell subsets in adults but was restricted only to the Th1-cTfh subset in children. Further, adults had higher levels of parasite-specific cTfh cells, and cTfh cells which produced more Th2-Tfh associated cytokine IL-4. Consistent with a role of higher Tfh cell activation in rapid immune development in adults, adults had higher activation of B cells during infection and higher induction of antibodies 7 and 28 days after malaria compared to children. Interpretation: Our data provide evidence that age impacts Tfh cell activation during malaria, and that these differences may influence antibody induction after treatment.

Findings have important implications for vaccine development in children. Funding: This word was supported by the National Health and Medical Research Council of Australia, Wellcome Trust, Charles Darwin University Menzies School of Health Research, Channel 7 Children's Research Foundation, and National Health Institute.

Original language	English
Article number	103784
Number of pages	22
Journal	EBioMedicine
Volume	75
DOIs	https://doi.org/10.1016/j.ebiom.2021.103784
Publication status	Published - Jan 2022

Bibliographical note

Funding Information:
We thank the Australian Red Cross Blood Service for providing malaria na?ve samples and RBC for parasite culture. We thank Robin Anders (La Trobe University) for the generous supply of recombinant PfMSP2-3D7. We thank staff of the Papuan Health and Community Development Foundation, and all staff and teams involved in the studies. We thank Ammar Aziz for providing bioinformatics support. This work was supported by the National Health and Medical Research Council of Australia (International Collaborative Research Grant 283321; Early Career Fellowship 1125656 and Career Development Award 1141278, Project Grant 1145303 to PMH and BW, and Project Grant 1125656 to MJB; Senior Principal Research Fellowship 1135820 to NMA; Program Grants 290208 and 1132975; Investigator Grant 1173046 to JGB); Wellcome Trust (International Collaborative Research Grant ME928457MES; Senior Fellowship 200909 to RNP); Charles Darwin University (PhD scholarship to DAO), Menzies School of Health Research (PhD top-up award to DAO), The Australian Centre of Research Excellence in Malaria Elimination (ACREME) (Training award to DAO), Channel 7 Children's Research Foundation (grant to MJB and GM) and National Health Institute (grant 5RO1 A1041764-08). The Burnet Institute is supported by the National Health and Medical Research Council for Independent Research Institutes Infrastructure Support Scheme and the Victorian State Government Operational Infrastructure Support.

Funding Information:
This work was supported by the National Health and Medical Research Council of Australia (International Collaborative Research Grant 283321; Early Career Fellowship 1125656 and Career Development Award 1141278, Project Grant 1145303 to PMH and BW, and Project Grant 1125656 to MJB; Senior Principal Research Fellowship 1135820 to NMA; Program Grants 290208 and 1132975; Investigator Grant 1173046 to JGB); Wellcome Trust (International Collaborative Research Grant ME928457MES; Senior Fellowship 200909 to RNP); Charles Darwin University (PhD scholarship to DAO), Menzies School of Health Research (PhD top-up award to DAO), The Australian Centre of Research Excellence in Malaria Elimination (ACREME) (Training award to DAO), Channel 7 Children's Research Foundation (grant to MJB and GM) and National Health Institute (grant 5RO1 A1041764-08). The Burnet Institute is supported by the National Health and Medical Research Council for Independent Research Institutes Infrastructure Support Scheme and the Victorian State Government Operational Infrastructure Support.

Publisher Copyright:
© 2021 The Authors

Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.

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Oyong, D. A., Loughland, J. R., Soon, M. S. F., Chan, J. A., Andrew, D., Wines, B. D., Hogarth, P. M., Olver, S. D., Collinge, A. D., Varelias, A., Beeson, J. G., Kenangalem, E., Price, R. N., Anstey, N. M., Minigo, G., & Boyle, M. J. (2022). Adults with Plasmodium falciparum malaria have higher magnitude and quality of circulating T-follicular helper cells compared to children. EBioMedicine, 75, Article 103784. https://doi.org/10.1016/j.ebiom.2021.103784

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title = "Adults with Plasmodium falciparum malaria have higher magnitude and quality of circulating T-follicular helper cells compared to children",

abstract = "Background: Protective malarial antibodies are acquired more rapidly in adults than children, independently of cumulative exposure, however the cellular responses mediating these differences are unknown. CD4 T-follicular helper (Tfh) cells have key roles in inducing antibodies, with Th2-Tfh cell activation associated with antibody development in malaria. Whether Tfh cell activation in malaria is age dependent is unknown and no studies have compared Tfh cell activation in children and adults with malaria. Methods: We undertook a comprehensive study of Tfh cells, along with B cells and antibody induction in children and adults with malaria. Activation and proliferation of circulating Tfh (cTfh) cell subsets was measured ex vivo and parasite-specific Tfh cell frequencies and functions studied with Activation Induced Marker (AIM) assays and intracellular cytokine staining. Findings: During acute malaria, the magnitude of cTfh cell activation was higher in adults than in children and occurred across all cTfh cell subsets in adults but was restricted only to the Th1-cTfh subset in children. Further, adults had higher levels of parasite-specific cTfh cells, and cTfh cells which produced more Th2-Tfh associated cytokine IL-4. Consistent with a role of higher Tfh cell activation in rapid immune development in adults, adults had higher activation of B cells during infection and higher induction of antibodies 7 and 28 days after malaria compared to children. Interpretation: Our data provide evidence that age impacts Tfh cell activation during malaria, and that these differences may influence antibody induction after treatment. Findings have important implications for vaccine development in children. Funding: This word was supported by the National Health and Medical Research Council of Australia, Wellcome Trust, Charles Darwin University Menzies School of Health Research, Channel 7 Children's Research Foundation, and National Health Institute.",

keywords = "antibodies, immunity, malaria, Plasmodium falciparum, T-follicular helper cells",

author = "Oyong, {Damian A.} and Loughland, {Jessica R.} and Soon, {Megan S.F.} and Chan, {Jo Anne} and Dean Andrew and Wines, {Bruce D.} and Hogarth, {P. Mark} and Olver, {Stuart D.} and Collinge, {Alika D.} and Antiopi Varelias and Beeson, {James G.} and Enny Kenangalem and Price, {Ric N.} and Anstey, {Nicholas M.} and Gabriela Minigo and Boyle, {Michelle J.}",

note = "Funding Information: We thank the Australian Red Cross Blood Service for providing malaria na?ve samples and RBC for parasite culture. We thank Robin Anders (La Trobe University) for the generous supply of recombinant PfMSP2-3D7. We thank staff of the Papuan Health and Community Development Foundation, and all staff and teams involved in the studies. We thank Ammar Aziz for providing bioinformatics support. This work was supported by the National Health and Medical Research Council of Australia (International Collaborative Research Grant 283321; Early Career Fellowship 1125656 and Career Development Award 1141278, Project Grant 1145303 to PMH and BW, and Project Grant 1125656 to MJB; Senior Principal Research Fellowship 1135820 to NMA; Program Grants 290208 and 1132975; Investigator Grant 1173046 to JGB); Wellcome Trust (International Collaborative Research Grant ME928457MES; Senior Fellowship 200909 to RNP); Charles Darwin University (PhD scholarship to DAO), Menzies School of Health Research (PhD top-up award to DAO), The Australian Centre of Research Excellence in Malaria Elimination (ACREME) (Training award to DAO), Channel 7 Children's Research Foundation (grant to MJB and GM) and National Health Institute (grant 5RO1 A1041764-08). The Burnet Institute is supported by the National Health and Medical Research Council for Independent Research Institutes Infrastructure Support Scheme and the Victorian State Government Operational Infrastructure Support. Funding Information: This work was supported by the National Health and Medical Research Council of Australia (International Collaborative Research Grant 283321; Early Career Fellowship 1125656 and Career Development Award 1141278, Project Grant 1145303 to PMH and BW, and Project Grant 1125656 to MJB; Senior Principal Research Fellowship 1135820 to NMA; Program Grants 290208 and 1132975; Investigator Grant 1173046 to JGB); Wellcome Trust (International Collaborative Research Grant ME928457MES; Senior Fellowship 200909 to RNP); Charles Darwin University (PhD scholarship to DAO), Menzies School of Health Research (PhD top-up award to DAO), The Australian Centre of Research Excellence in Malaria Elimination (ACREME) (Training award to DAO), Channel 7 Children's Research Foundation (grant to MJB and GM) and National Health Institute (grant 5RO1 A1041764-08). The Burnet Institute is supported by the National Health and Medical Research Council for Independent Research Institutes Infrastructure Support Scheme and the Victorian State Government Operational Infrastructure Support. Publisher Copyright: {\textcopyright} 2021 The Authors Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2022",

month = jan,

doi = "10.1016/j.ebiom.2021.103784",

language = "English",

volume = "75",

journal = "EBioMedicine",

issn = "2352-3964",

publisher = "Elsevier",

}

Oyong, DA, Loughland, JR, Soon, MSF, Chan, JA, Andrew, D, Wines, BD, Hogarth, PM, Olver, SD, Collinge, AD, Varelias, A, Beeson, JG, Kenangalem, E, Price, RN , Anstey, NM , Minigo, G & Boyle, MJ 2022, 'Adults with Plasmodium falciparum malaria have higher magnitude and quality of circulating T-follicular helper cells compared to children', EBioMedicine, vol. 75, 103784. https://doi.org/10.1016/j.ebiom.2021.103784

TY - JOUR

T1 - Adults with Plasmodium falciparum malaria have higher magnitude and quality of circulating T-follicular helper cells compared to children

AU - Oyong, Damian A.

AU - Loughland, Jessica R.

AU - Soon, Megan S.F.

AU - Chan, Jo Anne

AU - Andrew, Dean

AU - Wines, Bruce D.

AU - Hogarth, P. Mark

AU - Olver, Stuart D.

AU - Collinge, Alika D.

AU - Varelias, Antiopi

AU - Beeson, James G.

AU - Kenangalem, Enny

AU - Price, Ric N.

AU - Anstey, Nicholas M.

AU - Minigo, Gabriela

AU - Boyle, Michelle J.

N1 - Funding Information: We thank the Australian Red Cross Blood Service for providing malaria na?ve samples and RBC for parasite culture. We thank Robin Anders (La Trobe University) for the generous supply of recombinant PfMSP2-3D7. We thank staff of the Papuan Health and Community Development Foundation, and all staff and teams involved in the studies. We thank Ammar Aziz for providing bioinformatics support. This work was supported by the National Health and Medical Research Council of Australia (International Collaborative Research Grant 283321; Early Career Fellowship 1125656 and Career Development Award 1141278, Project Grant 1145303 to PMH and BW, and Project Grant 1125656 to MJB; Senior Principal Research Fellowship 1135820 to NMA; Program Grants 290208 and 1132975; Investigator Grant 1173046 to JGB); Wellcome Trust (International Collaborative Research Grant ME928457MES; Senior Fellowship 200909 to RNP); Charles Darwin University (PhD scholarship to DAO), Menzies School of Health Research (PhD top-up award to DAO), The Australian Centre of Research Excellence in Malaria Elimination (ACREME) (Training award to DAO), Channel 7 Children's Research Foundation (grant to MJB and GM) and National Health Institute (grant 5RO1 A1041764-08). The Burnet Institute is supported by the National Health and Medical Research Council for Independent Research Institutes Infrastructure Support Scheme and the Victorian State Government Operational Infrastructure Support. Funding Information: This work was supported by the National Health and Medical Research Council of Australia (International Collaborative Research Grant 283321; Early Career Fellowship 1125656 and Career Development Award 1141278, Project Grant 1145303 to PMH and BW, and Project Grant 1125656 to MJB; Senior Principal Research Fellowship 1135820 to NMA; Program Grants 290208 and 1132975; Investigator Grant 1173046 to JGB); Wellcome Trust (International Collaborative Research Grant ME928457MES; Senior Fellowship 200909 to RNP); Charles Darwin University (PhD scholarship to DAO), Menzies School of Health Research (PhD top-up award to DAO), The Australian Centre of Research Excellence in Malaria Elimination (ACREME) (Training award to DAO), Channel 7 Children's Research Foundation (grant to MJB and GM) and National Health Institute (grant 5RO1 A1041764-08). The Burnet Institute is supported by the National Health and Medical Research Council for Independent Research Institutes Infrastructure Support Scheme and the Victorian State Government Operational Infrastructure Support. Publisher Copyright: © 2021 The Authors Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2022/1

Y1 - 2022/1

N2 - Background: Protective malarial antibodies are acquired more rapidly in adults than children, independently of cumulative exposure, however the cellular responses mediating these differences are unknown. CD4 T-follicular helper (Tfh) cells have key roles in inducing antibodies, with Th2-Tfh cell activation associated with antibody development in malaria. Whether Tfh cell activation in malaria is age dependent is unknown and no studies have compared Tfh cell activation in children and adults with malaria. Methods: We undertook a comprehensive study of Tfh cells, along with B cells and antibody induction in children and adults with malaria. Activation and proliferation of circulating Tfh (cTfh) cell subsets was measured ex vivo and parasite-specific Tfh cell frequencies and functions studied with Activation Induced Marker (AIM) assays and intracellular cytokine staining. Findings: During acute malaria, the magnitude of cTfh cell activation was higher in adults than in children and occurred across all cTfh cell subsets in adults but was restricted only to the Th1-cTfh subset in children. Further, adults had higher levels of parasite-specific cTfh cells, and cTfh cells which produced more Th2-Tfh associated cytokine IL-4. Consistent with a role of higher Tfh cell activation in rapid immune development in adults, adults had higher activation of B cells during infection and higher induction of antibodies 7 and 28 days after malaria compared to children. Interpretation: Our data provide evidence that age impacts Tfh cell activation during malaria, and that these differences may influence antibody induction after treatment. Findings have important implications for vaccine development in children. Funding: This word was supported by the National Health and Medical Research Council of Australia, Wellcome Trust, Charles Darwin University Menzies School of Health Research, Channel 7 Children's Research Foundation, and National Health Institute.

AB - Background: Protective malarial antibodies are acquired more rapidly in adults than children, independently of cumulative exposure, however the cellular responses mediating these differences are unknown. CD4 T-follicular helper (Tfh) cells have key roles in inducing antibodies, with Th2-Tfh cell activation associated with antibody development in malaria. Whether Tfh cell activation in malaria is age dependent is unknown and no studies have compared Tfh cell activation in children and adults with malaria. Methods: We undertook a comprehensive study of Tfh cells, along with B cells and antibody induction in children and adults with malaria. Activation and proliferation of circulating Tfh (cTfh) cell subsets was measured ex vivo and parasite-specific Tfh cell frequencies and functions studied with Activation Induced Marker (AIM) assays and intracellular cytokine staining. Findings: During acute malaria, the magnitude of cTfh cell activation was higher in adults than in children and occurred across all cTfh cell subsets in adults but was restricted only to the Th1-cTfh subset in children. Further, adults had higher levels of parasite-specific cTfh cells, and cTfh cells which produced more Th2-Tfh associated cytokine IL-4. Consistent with a role of higher Tfh cell activation in rapid immune development in adults, adults had higher activation of B cells during infection and higher induction of antibodies 7 and 28 days after malaria compared to children. Interpretation: Our data provide evidence that age impacts Tfh cell activation during malaria, and that these differences may influence antibody induction after treatment. Findings have important implications for vaccine development in children. Funding: This word was supported by the National Health and Medical Research Council of Australia, Wellcome Trust, Charles Darwin University Menzies School of Health Research, Channel 7 Children's Research Foundation, and National Health Institute.

KW - antibodies

KW - immunity

KW - malaria

KW - Plasmodium falciparum

KW - T-follicular helper cells

UR - http://www.scopus.com/inward/record.url?scp=85121977415&partnerID=8YFLogxK

U2 - 10.1016/j.ebiom.2021.103784

DO - 10.1016/j.ebiom.2021.103784

M3 - Article

C2 - 34968760

AN - SCOPUS:85121977415

SN - 2352-3964

VL - 75

JO - EBioMedicine

JF - EBioMedicine

M1 - 103784

ER -

Adults with Plasmodium falciparum malaria have higher magnitude and quality of circulating T-follicular helper cells compared to children

Abstract

Bibliographical note

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