Th2 single-cell heterogeneity and clonal distribution at distant sites in helminth-infected mice

Abstract

Th2 cells provide effector functions in type 2 immune responses to helminths and allergens. Despite knowledge about molecular mechanisms of Th2 cell differentiation, there is little information on Th2 cell heterogeneity and clonal distribution between organs. To address this, we performed combined single-cell transcriptome and TCR clonotype analysis on murine Th2 cells in mesenteric lymph nodes (MLN) and lung after infection with Nippostrongylus brasiliensis (Nb) as a human hookworm infection model. We find organ-specific expression profiles, but also populations with conserved migration or effector/resident memory signatures that unexpectedly cluster with potentially regulatory Il10posFoxp3neg cells. A substantial MLN subpopulation with an interferon response signature suggests a role for interferon-signaling in Th2 differentiation or diversification. Further RNA-inferred developmental directions indicate proliferation as a hub for differentiation decisions. Although the TCR repertoire is highly heterogeneous, we identified expanded clones and CDR3 motifs. Clonal relatedness between distant organs confirmed effective exchange of Th2 effector cells, although locally expanded clones dominated the response. We further cloned an Nb-specific TCR from an expanded clone in the lung effector cluster and describe surface markers that distinguish transcriptionally defined clusters. These results provide insights in Th2 cell subset diversity and clonal relatedness in distant organs.

Data availability

Single-cell RNA sequencing data is available via GEO with the ID GSE181342

The following data sets were generated

Article and author information

Author details

  1. Daniel Radtke

    Department of Infection Biology, University of Erlangen-Nuremberg, Erlangen, Germany
    For correspondence
    daniel.radtke@uk-erlangen.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3241-4542
  2. Natalie Thuma

    Department of Infection Biology, University of Erlangen-Nuremberg, Erlangen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Christine Schülein

    Institute of Clinical Microbiology, University of Erlangen-Nuremberg, Erlangen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Philipp Kirchner

    Institute of Human Genetics, University of Erlangen-Nuremberg, Erlangen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Arif B Ekici

    Institute of Human Genetics, University of Erlangen-Nuremberg, Erlangen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Kilian Schober

    Institute of Clinical Microbiology, University of Erlangen-Nuremberg, Erlangen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  7. David Voehringer

    Department of Infection Biology, University of Erlangen-Nuremberg, Erlangen, Germany
    For correspondence
    David.Voehringer@uk-erlangen.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6650-0639

Funding

Deutsche Forschungsgemeinschaft (RTG1660)

  • David Voehringer

Deutsche Forschungsgemeinschaft (FOR2599_TP4)

  • David Voehringer

Deutsche Forschungsgemeinschaft (TRR130_TP20)

  • David Voehringer

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

Ethics

Animal experimentation: All experiments were performed in accordance with German animal protection law and European Union guidelines 86/809 and were approved by the Federal Government of Lower Franconia.

Reviewing Editor

  1. Bernard Malissen, Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université, France

Publication history

  1. Received: September 24, 2021
  2. Preprint posted: October 3, 2021 (view preprint)
  3. Accepted: August 10, 2022
  4. Accepted Manuscript published: August 11, 2022 (version 1)
  5. Version of Record published: August 19, 2022 (version 2)

Copyright

© 2022, Radtke 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. Daniel Radtke
  2. Natalie Thuma
  3. Christine Schülein
  4. Philipp Kirchner
  5. Arif B Ekici
  6. Kilian Schober
  7. David Voehringer
(2022)
Th2 single-cell heterogeneity and clonal distribution at distant sites in helminth-infected mice
eLife 11:e74183.
https://doi.org/10.7554/eLife.74183
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