Abstract
Introduction:
Follicular helper T cells are essential for helping in the maturation of B cells and the production of neutralizing antibodies (NAbs) during primary viral infections. However, their role during recall responses is unclear. Here, we used hepatitis C virus (HCV) reinfection in humans as a model to study the recall collaborative interaction between circulating CD4 T follicular helper cells (cTfh) and memory B cells (MBCs) leading to the generation of NAbs.
Methods:
We evaluated this interaction longitudinally in subjects who have spontaneously resolved primary HCV infection during a subsequent reinfection episode that resulted in either another spontaneous resolution (SR/SR, n = 14) or chronic infection (SR/CI, n = 8).
Results:
Both groups exhibited virus-specific memory T cells that expanded upon reinfection. However, early expansion of activated cTfh (CD4+CXCR5+PD-1+ICOS+FoxP3-) occurred in SR/SR only. The frequency of activated cTfh negatively correlated with time post-infection. Concomitantly, NAbs and HCV-specific MBCs (CD19+CD27+IgM-E2-Tet+) peaked during the early acute phase in SR/SR but not in SR/CI. Finally, the frequency of the activated cTfh1 (CXCR3+CCR6-) subset correlated with the neutralization breadth and potency of NAbs.
Conclusion:
These results underscore a key role for early activation of cTfh1 cells in helping antigen-specific B cells to produce NAbs that mediate the clearance of HCV reinfection.
Keywords:
B cells; Tfh and immunity; hepatitis C virus; neutralizing antibodies; reinfection.
Copyright © 2024 Eisa, Gomez-Escobar, Bédard, Abdeltawab, Flores, Mazouz, Fieffé-Bédard, Sakayan, Gridley, Abdel-Hakeem, Bruneau, Grakoui and Shoukry.
MeSH terms
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Adult
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Antibodies, Neutralizing / blood
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Antibodies, Neutralizing / immunology
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Female
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Hepacivirus* / immunology
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Hepatitis C Antibodies / blood
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Hepatitis C Antibodies / immunology
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Hepatitis C* / immunology
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Hepatitis C* / virology
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Hepatitis C, Chronic / immunology
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Hepatitis C, Chronic / virology
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Humans
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Immunologic Memory
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Lymphocyte Activation / immunology
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Male
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Memory B Cells* / immunology
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Middle Aged
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Reinfection* / immunology
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Reinfection* / virology
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T Follicular Helper Cells* / immunology
Substances
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Antibodies, Neutralizing
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Hepatitis C Antibodies
Grants and funding
The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by grants from the National Institutes of Health (NIH) U01AI131313 to NS, R01AI136533 and U19AI159819 to NS and AG, ORIP/OD P51OD011132 (formerly NCRR P51RR000165) to the Emory National Primate Research Center and the Monelli Foundation (AG), the Canadian Institutes of Health Research (CIHR) (PJT-173467) and Fonds de recherche du Québec–Santé (FRQS) AIDS and Infectious Disease Network (Réseau SIDAMI) (NS and JB). EG-E, SM, AF-B, and MA-H received fellowships from the Canadian Network on Hepatitis C (CanHepC). CanHepC is funded by a joint initiative of CIHR (HPC-178912) and the Public Health Agency of Canada. NA received postdoctoral short-term mission from the Egyptian Ministry of Higher Education Cultural Affairs and Mission Sector. AF-B received an undergraduate student research award from the Natural Sciences and Engineering Research Council of Canada (NSERC). JG was supported by the Emory Vaccinology Training grant T32 5T32AI074492-14. MA-H received doctoral fellowships from CIHR. JB is the Canada Research Chair in Addiction Medicine. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.