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BCL6-dependent TCF-1+ progenitor cells maintain effector and helper CD4 T cell responses to persistent antigen

View ORCID ProfileYu Xia, View ORCID ProfileKatalin Sandor, Joy A. Pai, View ORCID ProfileBence Daniel, View ORCID ProfileSaravanan Raju, Renee Wu, View ORCID ProfileSunnie Hsiung, Yanyan Qi, Tenzin Yangdon, View ORCID ProfileMariko Okamoto, Robert D. Schreiber, View ORCID ProfileKenneth M. Murphy, View ORCID ProfileAnsuman T. Satpathy, View ORCID ProfileTakeshi Egawa
doi: https://doi.org/10.1101/2021.08.06.455141
Yu Xia
1Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
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Katalin Sandor
2Department of Pathology, Stanford University, Stanford, CA 94305, USA
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Joy A. Pai
2Department of Pathology, Stanford University, Stanford, CA 94305, USA
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Bence Daniel
2Department of Pathology, Stanford University, Stanford, CA 94305, USA
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Saravanan Raju
1Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
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Renee Wu
1Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
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Sunnie Hsiung
1Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
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  • ORCID record for Sunnie Hsiung
Yanyan Qi
2Department of Pathology, Stanford University, Stanford, CA 94305, USA
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Tenzin Yangdon
1Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
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Mariko Okamoto
1Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
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  • ORCID record for Mariko Okamoto
Robert D. Schreiber
1Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
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Kenneth M. Murphy
1Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
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  • ORCID record for Kenneth M. Murphy
Ansuman T. Satpathy
2Department of Pathology, Stanford University, Stanford, CA 94305, USA
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  • For correspondence: satpathy@stanford.edu egawat@wustl.edu
Takeshi Egawa
1Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
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  • ORCID record for Takeshi Egawa
  • For correspondence: satpathy@stanford.edu egawat@wustl.edu
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Summary

Shortly after priming, the fate of activated CD4 T cells is segregated into BCL6+ follicular helper T (Tfh) and BCL6− effector (Teff) cells. However, it remains unknown how these subsets are sustained in the presence of chronic antigen stimulation. Using a combination of single cell- and population-based approaches, we show that in chronic viral infection, activated CD4 T cells differentiate into BCL6-dependent TCF-1+ progenitor cells with superior capacity to expand and give rise to both Teff and Tfh. They share properties with progenitor-exhausted CD8 T cells and are required for the continued generation of Teff cells as antigen persists. In response to tumors, an analogous CD4 T cell population develops in draining lymph nodes. Our study reveals the heterogeneity and plasticity of CD4 T cells upon encountering persistent antigen and highlights their population dynamics through a stable bipotent intermediate state.

Competing Interest Statement

A.T.S. is a scientific co-founder of Immunai and founder of Cartography Biosciences and receives research funding from Arsenal Biosciences and Allogene Therapeutics.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted August 09, 2021.
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BCL6-dependent TCF-1+ progenitor cells maintain effector and helper CD4 T cell responses to persistent antigen
Yu Xia, Katalin Sandor, Joy A. Pai, Bence Daniel, Saravanan Raju, Renee Wu, Sunnie Hsiung, Yanyan Qi, Tenzin Yangdon, Mariko Okamoto, Robert D. Schreiber, Kenneth M. Murphy, Ansuman T. Satpathy, Takeshi Egawa
bioRxiv 2021.08.06.455141; doi: https://doi.org/10.1101/2021.08.06.455141
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BCL6-dependent TCF-1+ progenitor cells maintain effector and helper CD4 T cell responses to persistent antigen
Yu Xia, Katalin Sandor, Joy A. Pai, Bence Daniel, Saravanan Raju, Renee Wu, Sunnie Hsiung, Yanyan Qi, Tenzin Yangdon, Mariko Okamoto, Robert D. Schreiber, Kenneth M. Murphy, Ansuman T. Satpathy, Takeshi Egawa
bioRxiv 2021.08.06.455141; doi: https://doi.org/10.1101/2021.08.06.455141

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