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IL-21 has a critical role in establishing germinal centers by amplifying early B cell proliferation

View ORCID ProfileAlexandra R. Dvorscek, View ORCID ProfileCraig I. McKenzie, View ORCID ProfileMarcus J. Robinson, View ORCID ProfileZhoujie Ding, Catherine Pitt, Kristy O’Donnell, Dimitra Zotos, View ORCID ProfileRobert Brink, View ORCID ProfileDavid M. Tarlinton, View ORCID ProfileIsaak Quast
doi: https://doi.org/10.1101/2022.01.21.476732
Alexandra R. Dvorscek
1Department of Immunology and Pathology, Monash University, 89 Commercial Rd, Melbourne 3004, Victoria, Australia
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Craig I. McKenzie
1Department of Immunology and Pathology, Monash University, 89 Commercial Rd, Melbourne 3004, Victoria, Australia
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Marcus J. Robinson
1Department of Immunology and Pathology, Monash University, 89 Commercial Rd, Melbourne 3004, Victoria, Australia
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Zhoujie Ding
1Department of Immunology and Pathology, Monash University, 89 Commercial Rd, Melbourne 3004, Victoria, Australia
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Catherine Pitt
1Department of Immunology and Pathology, Monash University, 89 Commercial Rd, Melbourne 3004, Victoria, Australia
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Kristy O’Donnell
1Department of Immunology and Pathology, Monash University, 89 Commercial Rd, Melbourne 3004, Victoria, Australia
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Dimitra Zotos
1Department of Immunology and Pathology, Monash University, 89 Commercial Rd, Melbourne 3004, Victoria, Australia
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Robert Brink
2Immunology Division, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia; St. Vincent’s Clinical School, UNSW Sydney, Sydney, NSW 2010, Australia
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David M. Tarlinton
1Department of Immunology and Pathology, Monash University, 89 Commercial Rd, Melbourne 3004, Victoria, Australia
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Isaak Quast
1Department of Immunology and Pathology, Monash University, 89 Commercial Rd, Melbourne 3004, Victoria, Australia
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  • For correspondence: isaak.quast@monash.edu
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Abstract

The proliferation and differentiation of antigen-specific B cells, including the generation of germinal centers (GC), are prerequisites for long-lasting, high-affinity antibody-mediated immune protection. Affinity for antigen determines B cell recruitment, proliferation, differentiation and competitiveness in the response, largely through determining access to T cell help. However, how T cell derived signals contribute to these outcomes is incompletely understood. Here we report how the signature cytokine of follicular helper T cells, IL-21, acts as a key regulator of the initial B cell response. By activating AKT and S6, IL-21 accelerates cell cycle progression and the rate of cycle entry of B cells, increasing their contribution to the ensuing GC. This effect occurs over a wide range of initial B cell receptor affinities and the resultant increased proliferation can explain the IL-21-mediated promotion of plasma cell differentiation. Collectively, our data establish that IL-21 acts from the outset of a T cell dependent immune response to increase cell cycle progression and fuel cyclic re-entry of B cells thereby regulating the initial GC size and early plasma cell output.

Summary The cytokine IL-21 is a regulator of B cell responses, increasing antibody quantity and quality. Here, we report that during germinal center initiation, IL-21 acts to increase the response magnitude by accelerating cell cycle speed and rate of entry.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • A detailed re-analysis of the initial manuscript revealed an analysis error that unfortunately had an impact on our final interpretation. In brief, a gating omission saw a very small number of additional but incorrect cells included in the SwHEL B cell gate. This affected only the response of IL21R deficient SwHEL B cells to HEL3xOVA and we have had to amend our conclusion that the effect of IL21 was strongest on low-affinity B cells in vivo. We now report that its role is in fact largely affinity-independent, acting as a ubiquitous response amplifier. We apologize unreservedly for this mistake and are confident in the robustness of the conclusions presented in this revised version. As such, the main conclusion of the manuscript, that IL21 plays a crucial and previously unrecognized role in B cell activation and in establishing the germinal center reaction, is now further strengthened by confirming that the shortfall in early expansion of IL21R deficient B cells indeed translates into deficits in mature germinal centers. Our new, added data also include the mechanistically highly relevant finding that IL21's property to increase plasma cell output is a consequence of its role in promoting B cell proliferation, rather than directly promoting plasma cell differentiation.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted May 11, 2022.
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IL-21 has a critical role in establishing germinal centers by amplifying early B cell proliferation
Alexandra R. Dvorscek, Craig I. McKenzie, Marcus J. Robinson, Zhoujie Ding, Catherine Pitt, Kristy O’Donnell, Dimitra Zotos, Robert Brink, David M. Tarlinton, Isaak Quast
bioRxiv 2022.01.21.476732; doi: https://doi.org/10.1101/2022.01.21.476732
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IL-21 has a critical role in establishing germinal centers by amplifying early B cell proliferation
Alexandra R. Dvorscek, Craig I. McKenzie, Marcus J. Robinson, Zhoujie Ding, Catherine Pitt, Kristy O’Donnell, Dimitra Zotos, Robert Brink, David M. Tarlinton, Isaak Quast
bioRxiv 2022.01.21.476732; doi: https://doi.org/10.1101/2022.01.21.476732

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