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A CD4+ T cell reference map delineates subtype-specific adaptation during acute and chronic viral infections

  1. Author:
    Andreatta, Massimo [ORCID]
    Tjitropranoto, Ariel [ORCID]
    Sherman, Zachary
    Kelly,Michael [ORCID]
    Ciucci, Thomas [ORCID]
    Carmona, Santiago J [ORCID]
  2. Author Address

    Agora Cancer Research Center, University of Lausanne, Lausanne, Switzerland., Department of Microbiology and Immunology, University of Rochester, Rochester, United States., Frederick National Laboratory for Cancer Research, Fregerick, United States.,
    1. Year: 2022
    2. Date: Jul 13
    3. Epub Date: 2022 07 13
  1. Journal: eLife
    1. 11
  2. Type of Article: Article
  1. Abstract:

    CD4+ T cells are critical orchestrators of immune responses against a large variety of pathogens, including viruses. The multifaceted roles of CD4+ T cells, including their help to innate cells, CD8+ T and B cells and their support for long-lived immunity rely on a profound functional heterogeneity. While multiple CD4+ T cell subtypes and their key transcriptional regulators have been identified, there is a lack of consistent definition for CD4+ T cell transcriptional states. In addition, the progressive changes affecting CD4+ T cell subtypes during and after immune responses remain poorly defined. Taking advantage of single-cell transcriptomics, efficient computational methods, and robust animal models, we characterize the transcriptional landscape of CD4+ T cells responding to self-resolving and chronic viral infections. We build a comprehensive map of virus-specific CD4+ T cells and their evolution over time, and identify six major distinct cell states that are consistently observed in acute and chronic infections in mice. During the course of acute infections, T cell composition progressively changes from effector to memory states, with subtype-specific gene modules and kinetics. Conversely, T cells in persistent infections fail to transition from effector to memory states, and acquire distinct, chronicity-associated transcriptional programs. By single-cell T cell receptor (TCR) sequencing analysis, we characterize the clonal structure of virus-specific CD4+ T cells across individuals and T cell subtypes. We find that virus-specific CD4+ T cell responses are essentially private across individuals and that most T cells differentiate into both Tfh and Th1 subtypes irrespective of their TCR, in both acute and chronic infections. Finally, we show that our CD4+ T cell map can be used as a reference to accurately interpret cell states in external single-cell datasets across tissues and disease models. Overall, this study describes a previously unappreciated level of adaptation of the transcriptional states of CD4+ T cells responding to viruses and provides a new computational resource for CD4+ T cell analysis, available online at https://spica.unil.ch.

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External Sources

  1. DOI: 10.7554/eLife.76339
  2. PMID: 35829695
  3. PII : 76339

Library Notes

  1. Fiscal Year: FY2021-2022
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