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Differentiation of exhausted CD8 T cells after termination of chronic antigen stimulation stops short of achieving functional T cell memory

View ORCID ProfilePierre Tonnerre, View ORCID ProfileDavid Wolski, View ORCID ProfileSonu Subudhi, Jihad Al-Jabban, Ruben C. Hoogeveen, Marcos Damasio, Hannah K. Drescher, Lea M. Bartsch, View ORCID ProfileDamien C. Tully, Debattama R. Sen, David J. Bean, Joelle Brown, Almudena Torres-Cornejo, Maxwell Robidoux, Daniel Kvistad, Nadia Alatrakchi, View ORCID ProfileAng Cui, David Lieb, James A. Cheney, Jenna Gustafson, Lia L Lewis-Ximenez, View ORCID ProfileLucile Massenet-Regad, Thomas Eisenhaure, Jasneet Aneja, W. Nicholas Haining, Raymond T. Chung, Nir Hacohen, Todd M. Allen, Arthur Y. Kim, View ORCID ProfileGeorg M. Lauer
doi: https://doi.org/10.1101/2021.04.03.437705
Pierre Tonnerre
1Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
2Inserm U976, Institut de Recherche Saint-Louis, Paris, France
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  • ORCID record for Pierre Tonnerre
  • For correspondence: glauer@mgh.harvard.edu pierre.tonnerre@inserm.fr
David Wolski
1Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
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  • ORCID record for David Wolski
Sonu Subudhi
1Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
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  • ORCID record for Sonu Subudhi
Jihad Al-Jabban
1Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
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Ruben C. Hoogeveen
1Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
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Marcos Damasio
1Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
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Hannah K. Drescher
1Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
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Lea M. Bartsch
1Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
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Damien C. Tully
3Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA
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  • ORCID record for Damien C. Tully
Debattama R. Sen
4Division of Medical Sciences, Harvard Medical School, Boston, MA, USA
5Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
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David J. Bean
3Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA
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Joelle Brown
1Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
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Almudena Torres-Cornejo
1Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
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Maxwell Robidoux
1Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
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Daniel Kvistad
1Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
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Nadia Alatrakchi
1Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
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Ang Cui
6Broad Institute of MIT and Harvard, Cambridge, MA, USA
7Harvard-MIT Division of Health Sciences and Technology, MIT, Cambridge, MA, USA
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David Lieb
6Broad Institute of MIT and Harvard, Cambridge, MA, USA
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James A. Cheney
1Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
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Jenna Gustafson
1Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
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Lia L Lewis-Ximenez
8Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
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Lucile Massenet-Regad
2Inserm U976, Institut de Recherche Saint-Louis, Paris, France
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  • ORCID record for Lucile Massenet-Regad
Thomas Eisenhaure
6Broad Institute of MIT and Harvard, Cambridge, MA, USA
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Jasneet Aneja
1Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
10Division of Infectious Diseases, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
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W. Nicholas Haining
4Division of Medical Sciences, Harvard Medical School, Boston, MA, USA
5Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
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Raymond T. Chung
1Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
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Nir Hacohen
6Broad Institute of MIT and Harvard, Cambridge, MA, USA
9Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA
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Todd M. Allen
3Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA
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Arthur Y. Kim
10Division of Infectious Diseases, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
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Georg M. Lauer
1Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
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  • ORCID record for Georg M. Lauer
  • For correspondence: glauer@mgh.harvard.edu pierre.tonnerre@inserm.fr
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Abstract

T cell exhaustion is associated with failure to clear chronic infections and malignant cells. Defining the molecular mechanisms of T cell exhaustion and reinvigoration is essential to improving immunotherapeutic modalities. Analysis of antigen-specific CD8+ T cells before and after antigen removal in human hepatitis C virus (HCV) infection confirmed pervasive phenotypic, functional, and transcriptional differences between exhausted and memory CD8+ T cells. After viral cure, we observed broad phenotypic and transcriptional changes in clonally stable exhausted T-cell populations suggesting differentiation towards a memory-like profile. However, functionally, the cells showed little improvement and critical transcriptional regulators remained in the exhaustion state. Notably, T cells from chronic HCV infection that were exposed to antigen for shorter periods of time because of viral escape mutations were functionally and transcriptionally more similar to memory T cells from spontaneously resolved acute HCV infection. Thus, duration of T cell stimulation impacts the ability to recover from exhaustion, as antigen removal after long-term T cell exhaustion is insufficient for the development of key T cell memory characteristics.

Competing Interest Statement

AbbVie sponsored the clinical trial (NCT02476617) and provided input to the trial design and clinical and biological sample collection schedule. W.N.H. is an employee of Merck and Company and holds equity in Tango Therapeutics and Arsenal Biosciences. All other authors declare no competing interests.

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 April 04, 2021.
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Differentiation of exhausted CD8 T cells after termination of chronic antigen stimulation stops short of achieving functional T cell memory
Pierre Tonnerre, David Wolski, Sonu Subudhi, Jihad Al-Jabban, Ruben C. Hoogeveen, Marcos Damasio, Hannah K. Drescher, Lea M. Bartsch, Damien C. Tully, Debattama R. Sen, David J. Bean, Joelle Brown, Almudena Torres-Cornejo, Maxwell Robidoux, Daniel Kvistad, Nadia Alatrakchi, Ang Cui, David Lieb, James A. Cheney, Jenna Gustafson, Lia L Lewis-Ximenez, Lucile Massenet-Regad, Thomas Eisenhaure, Jasneet Aneja, W. Nicholas Haining, Raymond T. Chung, Nir Hacohen, Todd M. Allen, Arthur Y. Kim, Georg M. Lauer
bioRxiv 2021.04.03.437705; doi: https://doi.org/10.1101/2021.04.03.437705
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Differentiation of exhausted CD8 T cells after termination of chronic antigen stimulation stops short of achieving functional T cell memory
Pierre Tonnerre, David Wolski, Sonu Subudhi, Jihad Al-Jabban, Ruben C. Hoogeveen, Marcos Damasio, Hannah K. Drescher, Lea M. Bartsch, Damien C. Tully, Debattama R. Sen, David J. Bean, Joelle Brown, Almudena Torres-Cornejo, Maxwell Robidoux, Daniel Kvistad, Nadia Alatrakchi, Ang Cui, David Lieb, James A. Cheney, Jenna Gustafson, Lia L Lewis-Ximenez, Lucile Massenet-Regad, Thomas Eisenhaure, Jasneet Aneja, W. Nicholas Haining, Raymond T. Chung, Nir Hacohen, Todd M. Allen, Arthur Y. Kim, Georg M. Lauer
bioRxiv 2021.04.03.437705; doi: https://doi.org/10.1101/2021.04.03.437705

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