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      T Cell Receptor Diversity and Lineage Relationship between Virus-Specific CD8 T Cell Subsets during Chronic Lymphocytic Choriomeningitis Virus Infection

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          Abstract

          CD8 TCR repertoires responding to chronic viral infections (HIV, hepatitis C virus [HCV], Epstein-Barr virus [EBV], and cytomegalovirus [CMV]) have limited breadth and diversity. How these repertoires change and are maintained throughout the chronic infection are unknown. We thus characterized the LCMV-specific CD8 TCR repertoires of stem-like and terminally exhausted subsets generated during chronic LCMV infections. During chronic LCMV infections, the repertoires started as diverse but became more clonal at the late time point. Further, the exhausted subset was composed of dominant clonotypes that were shared with the stem-like subset. Together, we demonstrate that the TCR repertoire contracts over time and is almost exclusively derived from the stem-like subset late during the persistent viral infection. Our data suggest that dominant clonotypes in the exhausted subset are derived from a diverse pool of stem-like clonotypes, which may be contributing to the clonality observed during chronic viral infections.

          ABSTRACT

          Recent studies on chronic viral infections have defined a novel programmed cell death 1-positive (PD-1 +) T cell factor 1-positive (TCF1 +) stem-like CD8 T cell subset that gives rise to the terminally differentiated exhausted CD8 T cells. In this study, we performed T cell receptor beta (TCRβ) sequencing of virus-specific CD8 T cells during chronic lymphocytic choriomeningitis virus (LCMV) infection to examine the TCR diversity and lineage relationship of these two functionally distinct subsets. We found that >95% of the TCR repertoire of the exhausted CD8 T cell subset was shared with the stem-like CD8 T cells. The TCR repertoires of both CD8 T cell subsets were composed mostly of a few dominant clonotypes, but there was slightly more breadth and diversity in the stem-like CD8 T cells than their exhausted counterpart (∼40 versus ∼15 GP33 + clonotypes; ∼20 versus ∼7 GP276 + clonotypes). Interestingly, the breadth of the TCR repertoire was broader during the early stages (day 8) of the chronic infection than the later stages (days 45 to 60), showing that there was a narrowing of the TCR repertoire during chronic infection (∼2-fold GP33 + and GP276 + stem-like subset; ∼10-fold GP33 + and ∼5-fold GP276 + exhausted subset). In contrast, during acute LCMV infection, the TCR repertoire was much broader in both GP33-specific effector (∼160 clonotypes) and memory CD8 T cells (∼160 clonotypes). Overall, our data demonstrate that the virus-specific CD8 T cell TCR repertoire is broad and remains stable after acute LCMV infection, but it contracts and is narrower during chronic infection. Our study also shows that the repertoire of the exhausted CD8 T cell subset is almost completely derived from the stem-like CD8 T cell subset during established chronic LCMV infection.

          IMPORTANCE CD8 TCR repertoires responding to chronic viral infections (HIV, hepatitis C virus [HCV], Epstein-Barr virus [EBV], and cytomegalovirus [CMV]) have limited breadth and diversity. How these repertoires change and are maintained throughout the chronic infection are unknown. We thus characterized the LCMV-specific CD8 TCR repertoires of stem-like and terminally exhausted subsets generated during chronic LCMV infections. During chronic LCMV infections, the repertoires started as diverse but became more clonal at the late time point. Further, the exhausted subset was composed of dominant clonotypes that were shared with the stem-like subset. Together, we demonstrate that the TCR repertoire contracts over time and is almost exclusively derived from the stem-like subset late during the persistent viral infection. Our data suggest that dominant clonotypes in the exhausted subset are derived from a diverse pool of stem-like clonotypes, which may be contributing to the clonality observed during chronic viral infections.

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          Author and article information

          Contributors
          Role: Editor
          Journal
          J Virol
          J. Virol
          jvi
          jvi
          JVI
          Journal of Virology
          American Society for Microbiology (1752 N St., N.W., Washington, DC )
          0022-538X
          1098-5514
          5 August 2020
          29 September 2020
          October 2020
          : 94
          : 20
          : e00935-20
          Affiliations
          [a ] Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia, USA
          [b ] Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA
          [c ] Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine, Atlanta, Georgia, USA
          [d ] Department of Biology, Emory University, Atlanta, Georgia, USA
          [e ] Department of Immunology, Sungkyunkwan University School of Medicine, Suwon, South Korea
          [f ] Department of Urology, Emory University School of Medicine, Atlanta, Georgia, USA
          University of North Carolina at Chapel Hill
          Author notes
          Address correspondence to Rafi Ahmed, rahmed@ 123456emory.edu .

          Citation Chang YM, Wieland A, Li Z-R, Im SJ, McGuire DJ, Kissick HT, Antia R, Ahmed R. 2020. T cell receptor diversity and lineage relationship between virus-specific CD8 T cell subsets during chronic lymphocytic choriomeningitis virus infection. J Virol 94:e00935-20. https://doi.org/10.1128/JVI.00935-20.

          Author information
          https://orcid.org/0000-0002-8766-3768
          https://orcid.org/0000-0003-0524-279X
          https://orcid.org/0000-0003-0223-1198
          Article
          PMC7527051 PMC7527051 7527051 00935-20
          10.1128/JVI.00935-20
          7527051
          32759317
          26921b61-1724-4d9b-95ba-c1e66f0bf7e4
          Copyright © 2020 American Society for Microbiology.

          All Rights Reserved.

          History
          : 12 May 2020
          : 24 July 2020
          Page count
          Figures: 6, Tables: 0, Equations: 0, References: 58, Pages: 13, Words: 7518
          Funding
          Funded by: Adaptive Biotechnologies;
          Award ID: Young Investigators Award
          Award Recipient :
          Funded by: HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID), https://doi.org/10.13039/100000060;
          Award ID: R01 AI030048
          Award Recipient :
          Funded by: HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID), https://doi.org/10.13039/100000060;
          Award ID: P01 AI056299
          Award Recipient :
          Categories
          Cellular Response to Infection
          Custom metadata
          October 2020

          T cell immunity,T cell exhaustion,chronic viral infection,lymphocytic choriomeningitis virus,T cell receptor

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