SMAD4 and TGFβ are architects of inverse genetic programs during fate-determination of antiviral CTLs

  1. Karthik Chandiran
  2. Jenny E Suarez-Ramirez
  3. Yinghong Hu
  4. Evan R Jellison
  5. Zenep Ugur
  6. Jun-Siong Low
  7. Bryan McDonald
  8. Susan M Kaech
  9. Linda S Cauley  Is a corresponding author
  1. University of Connecticut Health Center, United States
  2. Emory University, United States
  3. Yale University, Switzerland
  4. Salk Institute for Biological Studies, United States

Abstract

Transforming growth factor β (TGFβ) is an important differentiation factor for cytotoxic T lymphocytes (CTLs) and alters the expression levels of several of homing-receptors during infection. SMAD4 is part of the canonical signaling network used by members of the transforming growth factor family. For this study, genetically-modified mice were used to determine how SMAD4 and TGFβ receptor II (TGFβRII) participate in transcriptional-programing of pathogen-specific CTLs. We show that these molecules are essential components of opposing signaling mechanisms, and cooperatively regulate a collection of genes that determine whether specialized populations of pathogen-specific CTLs circulate around the body, or settle in peripheral tissues. TGFb uses a canonical SMAD-dependent signaling pathway to down-regulate Eomesodermin (EOMES), KLRG1 and CD62L, while CD103 is induced. Conversely, in vivo and in vitro data show that EOMES, KLRG1, CX3CR1 and CD62L are positively-regulated via SMAD4, while CD103 and Hobit are downregulated. Intravascular staining shows that signaling via SMAD4 promotes formation of terminally-differentiated CTLs that localize in the vasculature. Our data shows that inflammatory molecules play a key role in lineage-determination of pathogen-specific CTLs, and use SMAD-dependent signaling to alter the expression levels of multiple homing-receptors and transcription factors with known functions during memory formation.

Data availability

Sequencing data have been deposited in GEO under accession codes GSE151637Figure 3-source data 1 contain the numerical data used to generate the figures

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

Article and author information

Author details

  1. Karthik Chandiran

    Department of Immunology, University of Connecticut Health Center, Farmington, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2118-7946
  2. Jenny E Suarez-Ramirez

    Department of Immunology, University of Connecticut Health Center, Farmington, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Yinghong Hu

    Department of Microbiology and Immunology, Emory University, Atlanta, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Evan R Jellison

    Department of Immunology, University of Connecticut Health Center, Farmington, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Zenep Ugur

    Department of Immunology, University of Connecticut Health Center, Farmington, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Jun-Siong Low

    Department of Immunobiology, Yale University, Bellinzona, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  7. Bryan McDonald

    NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Susan M Kaech

    NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Linda S Cauley

    Department of Immunology, University of Connecticut Health Center, Farmington, United States
    For correspondence
    lcauley@uchc.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9488-0341

Funding

National Institute of Allergy and Infectious Diseases (R01 AI123864)

  • Susan M Kaech
  • Linda S Cauley

American association for Immunologists (AAI Careers in Immunology Fellowship)

  • Linda S Cauley

University of Connecticut Health Center (bridge funding)

  • Linda S Cauley

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

Reviewing Editor

  1. Urszula Krzych, Walter Reed Army Institute of Research, United States

Ethics

Animal experimentation: Experiments were performed in accordance with protocol AP-200531-0824 approved by the UCONN Health Institutional Animal Care and Use Committee (IACUC). Every effort was made to minimize suffering.

Version history

  1. Preprint posted: December 16, 2021 (view preprint)
  2. Received: December 17, 2021
  3. Accepted: August 5, 2022
  4. Accepted Manuscript published: August 9, 2022 (version 1)
  5. Accepted Manuscript updated: August 11, 2022 (version 2)
  6. Version of Record published: August 24, 2022 (version 3)
  7. Version of Record updated: August 30, 2022 (version 4)

Copyright

© 2022, Chandiran 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. Karthik Chandiran
  2. Jenny E Suarez-Ramirez
  3. Yinghong Hu
  4. Evan R Jellison
  5. Zenep Ugur
  6. Jun-Siong Low
  7. Bryan McDonald
  8. Susan M Kaech
  9. Linda S Cauley
(2022)
SMAD4 and TGFβ are architects of inverse genetic programs during fate-determination of antiviral CTLs
eLife 11:e76457.
https://doi.org/10.7554/eLife.76457

Share this article

https://doi.org/10.7554/eLife.76457

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