Latent viral infections rely on a precise coordination of the immune response to control sporadic viral reactivation. CD8+ T cells play a crucial role in controlling viral latency by generating diverse memory responses in an epitope-specific manner. Among these distinct responses, conventional and inflationary memory responses have been described during herpesvirus infections. Using a newly generated TCR transgenic mouse strain, we investigated the transcriptomic and epigenetic remodeling of distinct epitope-specific CD8+ T cells during CMV infection across tissues at both population and single-cell levels. Our findings reveal that whereas the transcriptomic and epigenetic landscapes of conventional and inflationary memory responses diverge in the spleen and liver, these molecular programs converge in the salivary gland, a site of CMV persistence. Thus, we provide evidence that the dynamics of memory CD8+ T cell responses are distinct between tissues.
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May 19 2025
Defining molecular circuits of CD8+ T cell responses in tissues during latent viral infection
Endi K. Santosa
,
Endi K. Santosa
(Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Validation, Visualization, Writing - original draft, Writing - review & editing)
1
Immunology Program, Memorial Sloan Kettering Cancer Center
, New York, NY, USA
2
Immunology and Microbial Pathogenesis Program, Weill Cornell Medical College and Graduate School of Medical Sciences of Cornell University
, New York, NY, USA
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Jennifer M. Zhang
,
Jennifer M. Zhang
(Investigation, Writing - review & editing)
1
Immunology Program, Memorial Sloan Kettering Cancer Center
, New York, NY, USA
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John C. Sauter
,
John C. Sauter
(Investigation)
1
Immunology Program, Memorial Sloan Kettering Cancer Center
, New York, NY, USA
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Mariah E. Lee
,
Mariah E. Lee
(Investigation)
1
Immunology Program, Memorial Sloan Kettering Cancer Center
, New York, NY, USA
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Brandon D. Ng
,
Brandon D. Ng
(Investigation, Methodology)
1
Immunology Program, Memorial Sloan Kettering Cancer Center
, New York, NY, USA
3
Pharmacology Program, Weill Cornell Medical College and Graduate School of Medical Sciences of Cornell University
, New York, NY, USA
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Sigrun V. Stulz
,
Sigrun V. Stulz
(Formal analysis, Investigation)
4
Würzburg Institute of Systems Immunology, Max Planck Research Group at the Julius-Maximilians-Universität Würzburg
, Würzburg, Germany
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Meril Takizawa
,
Meril Takizawa
(Investigation)
5
Single Cell Analytics Innovation Lab, Memorial Sloan Kettering Cancer Center
, New York, NY, USA
6
Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center
, New York, NY, USA
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Simon Grassmann
,
Simon Grassmann
(Investigation)
1
Immunology Program, Memorial Sloan Kettering Cancer Center
, New York, NY, USA
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Orr-El Weizman
,
Orr-El Weizman
(Investigation)
1
Immunology Program, Memorial Sloan Kettering Cancer Center
, New York, NY, USA
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Nicholas M. Adams
,
Nicholas M. Adams
(Investigation)
7Department of Pathology,
New York University Grossman School of Medicine
, New York, NY, USA
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Ronan Chaligné
,
Ronan Chaligné
(Supervision)
5
Single Cell Analytics Innovation Lab, Memorial Sloan Kettering Cancer Center
, New York, NY, USA
6
Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center
, New York, NY, USA
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Annette Oxenius
,
Annette Oxenius
(Resources, Writing - original draft, Writing - review & editing)
8
Institute of Microbiology, ETH Zürich
, Zürich, Switzerland
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Georg Gasteiger
,
Georg Gasteiger
(Supervision)
4
Würzburg Institute of Systems Immunology, Max Planck Research Group at the Julius-Maximilians-Universität Würzburg
, Würzburg, Germany
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Colleen M. Lau
,
Colleen M. Lau
(Data curation, Formal analysis, Methodology, Resources, Software)
9Department of Microbiology and Immunology,
College of Veterinary Medicine of Cornell University
, Ithaca, NY, USA
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Joseph C. Sun
(Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing)
1
Immunology Program, Memorial Sloan Kettering Cancer Center
, New York, NY, USA
2
Immunology and Microbial Pathogenesis Program, Weill Cornell Medical College and Graduate School of Medical Sciences of Cornell University
, New York, NY, USA
Correspondence to Joseph C. Sun: [email protected]
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Endi K. Santosa
Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Validation, Visualization, Writing - original draft, Writing - review & editing
1
Immunology Program, Memorial Sloan Kettering Cancer Center
, New York, NY, USA
2
Immunology and Microbial Pathogenesis Program, Weill Cornell Medical College and Graduate School of Medical Sciences of Cornell University
, New York, NY, USA
Jennifer M. Zhang
Investigation, Writing - review & editing
1
Immunology Program, Memorial Sloan Kettering Cancer Center
, New York, NY, USA
John C. Sauter
Investigation
1
Immunology Program, Memorial Sloan Kettering Cancer Center
, New York, NY, USA
Mariah E. Lee
Investigation
1
Immunology Program, Memorial Sloan Kettering Cancer Center
, New York, NY, USA
Brandon D. Ng
Investigation, Methodology
1
Immunology Program, Memorial Sloan Kettering Cancer Center
, New York, NY, USA
3
Pharmacology Program, Weill Cornell Medical College and Graduate School of Medical Sciences of Cornell University
, New York, NY, USA
Sigrun V. Stulz
Formal analysis, Investigation
4
Würzburg Institute of Systems Immunology, Max Planck Research Group at the Julius-Maximilians-Universität Würzburg
, Würzburg, Germany
Meril Takizawa
Investigation
5
Single Cell Analytics Innovation Lab, Memorial Sloan Kettering Cancer Center
, New York, NY, USA
6
Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center
, New York, NY, USA
Simon Grassmann
Investigation
1
Immunology Program, Memorial Sloan Kettering Cancer Center
, New York, NY, USA
Orr-El Weizman
Investigation
1
Immunology Program, Memorial Sloan Kettering Cancer Center
, New York, NY, USA
Nicholas M. Adams
Investigation
7Department of Pathology,
New York University Grossman School of Medicine
, New York, NY, USA
Ronan Chaligné
Supervision
5
Single Cell Analytics Innovation Lab, Memorial Sloan Kettering Cancer Center
, New York, NY, USA
6
Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center
, New York, NY, USA
Annette Oxenius
Resources, Writing - original draft, Writing - review & editing
8
Institute of Microbiology, ETH Zürich
, Zürich, Switzerland
Georg Gasteiger
Supervision
4
Würzburg Institute of Systems Immunology, Max Planck Research Group at the Julius-Maximilians-Universität Würzburg
, Würzburg, Germany
Colleen M. Lau
Data curation, Formal analysis, Methodology, Resources, Software
9Department of Microbiology and Immunology,
College of Veterinary Medicine of Cornell University
, Ithaca, NY, USA
Joseph C. Sun
Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing
1
Immunology Program, Memorial Sloan Kettering Cancer Center
, New York, NY, USA
2
Immunology and Microbial Pathogenesis Program, Weill Cornell Medical College and Graduate School of Medical Sciences of Cornell University
, New York, NY, USA
Correspondence to Joseph C. Sun: [email protected]
Disclosures: The authors declare no competing interests exist.
Received:
November 05 2024
Revision Received:
March 18 2025
Accepted:
April 29 2025
Online ISSN: 1540-9538
Print ISSN: 0022-1007
Funding
Funder(s):
National Cancer Institute
- Award Id(s): P30CA008748
Funder(s):
Marie-Josée and Henry R. Karvis Center for Molecular Oncology
Funder(s):
Ludwig Center for Cancer Immunotherapy
Funder(s):
American Cancer Society
Funder(s):
Burroughs Wellcome Fund
Funder(s):
National Institutes of Health
- Award Id(s): AI100874,AI130043,AI155558,P30CA008748
© 2025 Santosa et al.
2025
Santosa et al.
This article is distributed under the terms as described at https://rupress.org/pages/terms102024/.
J Exp Med (2025) 222 (8): e20242078.
Article history
Received:
November 05 2024
Revision Received:
March 18 2025
Accepted:
April 29 2025
Citation
Endi K. Santosa, Jennifer M. Zhang, John C. Sauter, Mariah E. Lee, Brandon D. Ng, Sigrun V. Stulz, Meril Takizawa, Simon Grassmann, Orr-El Weizman, Nicholas M. Adams, Ronan Chaligné, Annette Oxenius, Georg Gasteiger, Colleen M. Lau, Joseph C. Sun; Defining molecular circuits of CD8+ T cell responses in tissues during latent viral infection. J Exp Med 4 August 2025; 222 (8): e20242078. doi: https://doi.org/10.1084/jem.20242078
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