Delineating the transcriptional landscape and clonal diversity of virus-specific CD4+ T cells during chronic viral infection

  1. Ryan Zander  Is a corresponding author
  2. Achia Khatun
  3. Moujtaba Y Kasmani
  4. Yao Chen
  5. Weiguo Cui  Is a corresponding author
  1. Versiti Blood Center of Wisconsin, United States
  2. Medical College of Wisconsin, United States

Abstract

CD4+ T cells responding to chronic viral infection often acquire a dysfunctional phenotype that is characterized by a progressive loss in Th1 differentiation and function, as well as an upregulation of multiple co-inhibitory receptors. Conversely, CD4+ T cells, and particularly Tfh cells, gradually increase their production of IL-21 during chronic viral infection, which is critical to sustain humoral immunity and also effector CD8+ T cell responses. Recent evidence further indicates that a memory-like CD4+ T cell population also develops in the face of persistent infection, although how the transcriptional landscape of this subset, along with the Th1 and Tfh cell subsets from chronic infection, differ from their acute infection counterparts remains unclear. Additionally, whether cell-intrinsic factors such as TCR usage influence CD4+ T cell fate commitment during chronic infection has not previously been studied. Herein, we perform single-cell RNA sequencing (scRNA-seq) combined with single-cell T cell receptor sequencing (scTCR-seq) on virus-specific CD4+ T cells isolated from mice infected with chronic lymphocytic choriomeningitis virus (LCMV) infection. We identify several transcriptionally distinct states among the Th1, Tfh, and memory-like T cell subsets that form at the peak of chronic infection, including the presence of a previously unrecognized Slamf7+ subset with cytolytic features, and show that the relative distribution of these populations differs substantially between acute and persistent LCMV infection. Moreover, while the progeny of most T cell clones displays membership within each of these transcriptionally unique populations, overall supporting a one cell-multiple fate model, a small fraction of clones display a biased cell fate decision, suggesting that TCR usage may impact CD4+ T cell development during chronic viral infection. Importantly, a comparative analysis further reveals both subset-specific and core gene expression programs that are differentially regulated between CD4+ T cells responding to acute and chronic viral infection. Together, these data may serve as a useful framework and allow for a detailed interrogation into the clonal distribution and transcriptional circuits underlying CD4+ T cell differentiation during chronic viral infection.

Data availability

The scRNA-seq and scTCR-seq data have been deposited in the GEO database (accession no GSE201730), and are available to the public.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Ryan Zander

    Blood Research Institute, Versiti Blood Center of Wisconsin, Milwaukee, United States
    For correspondence
    Ryan-Zander@uiowa.edu
    Competing interests
    The authors declare that no competing interests exist.
  2. Achia Khatun

    Blood Research Institute, Versiti Blood Center of Wisconsin, Milwaukee, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Moujtaba Y Kasmani

    Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5753-5335
  4. Yao Chen

    Blood Research Institute, Versiti Blood Center of Wisconsin, Milwaukee, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Weiguo Cui

    Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, United States
    For correspondence
    weiguo.cui@bcw.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1562-9218

Funding

NIH NIAID (R01 AI125741,R01 AI148403)

  • Weiguo Cui

NIH NIAID (K99/R00 AI153537)

  • Ryan Zander

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Kellie N Smith, The Johns Hopkins University School of Medicine, United States

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. Mice were bred and maintained in a closed breeding facility, and mouse handling conformed to the requirements of the Institutional Animal Care and Use Committee guidelines of the Medical College of Wisconsin. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#'s 00003003 & 00003004) of the Medical College of Wisconsin.

Version history

  1. Received: May 7, 2022
  2. Preprint posted: May 12, 2022 (view preprint)
  3. Accepted: October 17, 2022
  4. Accepted Manuscript published: October 18, 2022 (version 1)
  5. Version of Record published: November 2, 2022 (version 2)

Copyright

© 2022, Zander et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Ryan Zander
  2. Achia Khatun
  3. Moujtaba Y Kasmani
  4. Yao Chen
  5. Weiguo Cui
(2022)
Delineating the transcriptional landscape and clonal diversity of virus-specific CD4+ T cells during chronic viral infection
eLife 11:e80079.
https://doi.org/10.7554/eLife.80079

Share this article

https://doi.org/10.7554/eLife.80079

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