Enhancing and inhibitory motifs regulate CD4 activity
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.
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).
Data associated with "Enhancing and inhibitory motifs have coevolved to regulate CD4 activity"Dryad Digital Repository, doi:10.5061/dryad.59zw3r26z.
Article and author information
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.
- Richard N McLaughlin, Pacific Northwest Research Institute, United States
- Preprint posted: April 30, 2021 (view preprint)
- Received: April 15, 2022
- Accepted: July 20, 2022
- Accepted Manuscript published: July 21, 2022 (version 1)
- Version of Record published: July 28, 2022 (version 2)
© 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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