1. Chromosomes and Gene Expression
  2. Immunology and Inflammation

Alternative splicing of apoptosis genes promotes human T cell survival

  1. Davia Blake
  2. Caleb M Radens
  3. Max B Ferretti
  4. Matthew R Gazzara
  5. Kristen W Lynch  Is a corresponding author
  1. University of Pennsylvania, United States
https://doi.org/10.7554/eLife.80953
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  1. Davia Blake
  2. Caleb M Radens
  3. Max B Ferretti
  4. Matthew R Gazzara
  5. Kristen W Lynch
(2022)
Alternative splicing of apoptosis genes promotes human T cell survival
eLife 11:e80953.
https://doi.org/10.7554/eLife.80953
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Abstract

Alternative splicing occurs in the vast majority of human genes, giving rise to distinct mRNA and protein isoforms. We, and others, have previously identified hundreds of genes that change their isoform expression upon T cell activation via alternative splicing; however, how these changes link activation input with functional output remains largely unknown. Here we investigate how costimulation of T cells through the CD28 receptor impacts alternative splicing in T cells activated through the T cell receptor (CD3) and find that while CD28 signaling alone has minimal impact on splicing, it enhances the extent of change for up to 20% of TCR-induced alternative splicing events. Interestingly, a set of CD28-enhanced splicing events occur within genes encoding key components of the apoptotic signaling pathway; namely caspase-9, Bax and Bim. Using both CRISPR-edited cells and antisense oligos to force expression of specific isoforms, we show for all three of these genes that the isoform induced by CD3/CD28 costimulation promotes resistance to apoptosis, and that changes in all three genes together function combinatorially to further promote cell viability. Finally, we show that the JNK signaling pathway, induced downstream of CD3/CD28 costimulation, is required for each of these splicing events, further highlighting their co-regulation. Together these findings demonstrate that alternative splicing is a key mechanism by which costimulation of CD28 promotes viability of activated T cells.

Data availability

The RNA-seq data generated for this study is available in GEO under accession codes GSE135118.

The following data sets were generated

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Author details

  1. Davia Blake

    Immunology Graduate Group, University of Pennsylvania, Philadelphia, United States
    Competing interests
    No competing interests declared.

  2. Caleb M Radens

    Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, United States
    Competing interests
    No competing interests declared.

  3. Max B Ferretti

    Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, United States
    Competing interests
    No competing interests declared.

  4. Matthew R Gazzara

    Department of Genetics, University of Pennsylvania, Phildelphia, United States
    Competing interests
    No competing interests declared.

  5. Kristen W Lynch

    Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, United States
    For correspondence
    klync@pennmedicine.upenn.edu
    Competing interests
    Kristen W Lynch, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0120-8079

Funding

National Institute of General Medical Sciences (R35 GM118048)

  • Kristen W Lynch

National Institute of General Medical Sciences (F31 GM140978)

  • Davia Blake

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

Copyright

© 2022, Blake 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. Davia Blake
  2. Caleb M Radens
  3. Max B Ferretti
  4. Matthew R Gazzara
  5. Kristen W Lynch
(2022)
Alternative splicing of apoptosis genes promotes human T cell survival
eLife 11:e80953.
https://doi.org/10.7554/eLife.80953

Share this article

https://doi.org/10.7554/eLife.80953

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