Alternative splicing of apoptosis genes promotes human T cell survival
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 activ...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2022-10-01
|
| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/80953 |
| _version_ | 1811332701196648448 |
|---|---|
| author | Davia Blake Caleb M Radens Max B Ferretti Matthew R Gazzara Kristen W Lynch |
| author_facet | Davia Blake Caleb M Radens Max B Ferretti Matthew R Gazzara Kristen W Lynch |
| author_sort | Davia Blake |
| collection | DOAJ |
| description | 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 (TCR, 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. |
| first_indexed | 2024-04-13T16:40:01Z |
| format | Article |
| id | doaj.art-75407e14fee84819bfd252426750416b |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-13T16:40:01Z |
| publishDate | 2022-10-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-75407e14fee84819bfd252426750416b2022-12-22T02:39:15ZengeLife Sciences Publications LtdeLife2050-084X2022-10-011110.7554/eLife.80953Alternative splicing of apoptosis genes promotes human T cell survivalDavia Blake0Caleb M Radens1Max B Ferretti2Matthew R Gazzara3Kristen W Lynch4https://orcid.org/0000-0002-0120-8079Immunology Graduate Group, University of Pennsylvania, Philadelphia, United States; Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, United StatesDepartment of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, United StatesDepartment of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, United StatesDepartment of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, United States; Department of Genetics, University of Pennsylvania, Phildelphia, United StatesImmunology Graduate Group, University of Pennsylvania, Philadelphia, United States; Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, United StatesAlternative 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 (TCR, 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.https://elifesciences.org/articles/80953alternative splicinglymphocytesapoptosis |
| spellingShingle | Davia Blake Caleb M Radens Max B Ferretti Matthew R Gazzara Kristen W Lynch Alternative splicing of apoptosis genes promotes human T cell survival eLife alternative splicing lymphocytes apoptosis |
| title | Alternative splicing of apoptosis genes promotes human T cell survival |
| title_full | Alternative splicing of apoptosis genes promotes human T cell survival |
| title_fullStr | Alternative splicing of apoptosis genes promotes human T cell survival |
| title_full_unstemmed | Alternative splicing of apoptosis genes promotes human T cell survival |
| title_short | Alternative splicing of apoptosis genes promotes human T cell survival |
| title_sort | alternative splicing of apoptosis genes promotes human t cell survival |
| topic | alternative splicing lymphocytes apoptosis |
| url | https://elifesciences.org/articles/80953 |
| work_keys_str_mv | AT daviablake alternativesplicingofapoptosisgenespromoteshumantcellsurvival AT calebmradens alternativesplicingofapoptosisgenespromoteshumantcellsurvival AT maxbferretti alternativesplicingofapoptosisgenespromoteshumantcellsurvival AT matthewrgazzara alternativesplicingofapoptosisgenespromoteshumantcellsurvival AT kristenwlynch alternativesplicingofapoptosisgenespromoteshumantcellsurvival |