1. Evolutionary Biology
  2. Immunology and Inflammation

Enhancing and inhibitory motifs regulate CD4 activity

  1. Mark S Lee
  2. Peter J Tuohy
  3. Caleb Y Kim
  4. Katrina Lichauco
  5. Heather L Parrish
  6. Koenraad Van Doorslaer  Is a corresponding author
  7. Michael S Kuhns  Is a corresponding author
  1. University of Arizona College of Medicine, United States
  2. University of Arizona, United States
https://doi.org/10.7554/eLife.79508
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Cite this article
  1. Mark S Lee
  2. Peter J Tuohy
  3. Caleb Y Kim
  4. Katrina Lichauco
  5. Heather L Parrish
  6. Koenraad Van Doorslaer
  7. Michael S Kuhns
(2022)
Enhancing and inhibitory motifs regulate CD4 activity
eLife 11:e79508.
https://doi.org/10.7554/eLife.79508
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Abstract

CD4+ T cells use T cell receptor (TCR)-CD3 complexes, and CD4, to respond to peptide antigens within MHCII molecules (pMHCII). We report here that, through ~435 million years of evolution in jawed vertebrates, purifying selection has shaped motifs in the extracellular, transmembrane, and intracellular domains of eutherian CD4 that enhance pMHCII responses, and covary with residues in an intracellular motif that inhibits responses. Importantly, while CD4 interactions with the Src kinase, Lck, are viewed as key to pMHCII responses, our data indicate that CD4-Lck interactions derive their importance from the counterbalancing activity of the inhibitory motif, as well as motifs that direct CD4-Lck pairs to specific membrane compartments. These results have implications for the evolution and function of complex transmembrane receptors and for biomimetic engineering.

Data availability

Raw data, including alignments and phylogenetic trees, associated with figures 1 and S1 as well as source data and statistics for remaining figures are available on Dryad (https://doi.org/10.5061/dryad.59zw3r26z).

The following data sets were generated

Article and author information

Author details

  1. Mark S Lee

    Department of Immunobiology, University of Arizona College of Medicine, Tucson, United States
    Competing interests
    No competing interests declared.

  2. Peter J Tuohy

    Department of Immunobiology, University of Arizona College of Medicine, Tucson, United States
    Competing interests
    No competing interests declared.

  3. Caleb Y Kim

    Department of Immunobiology, University of Arizona College of Medicine, Tucson, United States
    Competing interests
    No competing interests declared.

  4. Katrina Lichauco

    Department of Immunobiology, University of Arizona College of Medicine, Tucson, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9480-2893

  5. Heather L Parrish

    Department of Immunobiology, University of Arizona College of Medicine, Tucson, United States
    Competing interests
    No competing interests declared.

  6. Koenraad Van Doorslaer

    School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, United States
    For correspondence
    vandoorslaer@arizona.edu
    Competing interests
    No competing interests declared.

  7. Michael S Kuhns

    Department of Immunobiology, University of Arizona College of Medicine, Tucson, United States
    For correspondence
    mkuhns@email.arizona.edu
    Competing interests
    Michael S Kuhns, has disclosed an outside interest in Module Therapeutics to the University of Arizona. Conflicts of interest resulting from this interest are being managed by the University of Arizona in accordance with their policies..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0403-6313

Funding

National Institute of Allergy and Infectious Diseases (R01AI101053)

  • Michael S Kuhns

Cancer Center Support Grant (CCSG-CA 023074)

  • Michael S Kuhns

AZ TRIF Funds

  • Koenraad Van Doorslaer

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

Copyright

© 2022, Lee 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. Mark S Lee
  2. Peter J Tuohy
  3. Caleb Y Kim
  4. Katrina Lichauco
  5. Heather L Parrish
  6. Koenraad Van Doorslaer
  7. Michael S Kuhns
(2022)
Enhancing and inhibitory motifs regulate CD4 activity
eLife 11:e79508.
https://doi.org/10.7554/eLife.79508

Share this article

https://doi.org/10.7554/eLife.79508

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Further reading

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    The CD4 transmembrane GGXXG and juxtamembrane (C/F)CV+C motifs mediate pMHCII-specific signaling independently of CD4-LCK interactions

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