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| Status |
Public on Nov 05, 2023 |
| Title |
TGF-β broadly modifies rather than specifically suppresses reactivated memory CD8 T cells in a dose-dependent manner (ATAC-Seq) |
| Organism |
Mus musculus |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
Transforming growth factor β (TGF-β) directly acts on naïve, effector and memory T cells to control cell fate decisions, which was shown using genetic abrogation of TGF-β signaling. TGF-β availability is altered by infections and cancer, however the dose-dependent effects of TGF-β on memory CD8 T cell (Tmem) reactivation are still poorly defined. We examined how activation and TGF-β signals interact to shape the functional outcome of Tmem reactivation. We found that TGF-β could suppress cytotoxicity in a manner that was inversely proportional to the strength of the activating TCR or pro-inflammatory signals. In contrast, even high doses of TGF-β had a comparatively modest effect on IFN-γ expression in the context of weak and strong reactivation signals. Since CD8 Tmem may not always receive TGF-β signals concurrently with reactivation, we also explored whether the temporal order of reactivation versus TGF-β signals is of importance. We found that exposure to TGF-β prior to as well as after an activation event were both sufficient to reduce cytotoxic effector function. Concurrent ATAC-seq and RNA-seq analysis revealed that TGF-β altered ~10% of the regulatory elements induced by reactivation and also elicited transcriptional changes indicative of broadly modulated functional properties. We confirmed some changes on the protein level and found that TGF-β-induced expression of CCR8 was inversely proportional to the strength of the reactivating TCR signal. Together, our data suggest that TGF-β is not simply suppressing CD8 Tmem, but modifies functional and chemotactic properties in context of their reactivation signals and in a dose-dependent manner.
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| Overall design |
OT-1 memory mice were harvested for secondary lymphoid organs (lymph nodes and spleen). A T cell isolation was performed to isolate T cells. T cells were plated for 2 hours with or without TGFb and for 24 hours with SIINFEKL and TGFb or SIINFEKL alone. OT-1 cells (CD45.1 and CD8+) were FACS sorted for downstream analysis by bulk RNAseq and bulk ATACseq.
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| Web link |
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10691214/
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| Contributor(s) |
Taber A, Konecny AJ, Oda S, Scott-Browne J, Prlic M |
| Citation(s) |
37988468 |
| NIH grant(s) |
| Grant ID |
Grant title |
Affiliation |
Name |
| R01 AI123323 |
Inflammation-driven T Cell Responses and their Dichotomous Effect on Host Immunity |
FRED HUTCHINSON CANCER CENTER |
Martin Prlic |
| R01 AI151021 |
Transcriptional Control of T Cell Function |
NATIONAL JEWISH HEALTH |
James Scott-Browne |
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| Submission date |
Nov 02, 2023 |
| Last update date |
Feb 05, 2024 |
| Contact name |
Martin Prlic |
| E-mail(s) |
mprlic@fredhutch.org
|
| Phone |
2066672216
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| Organization name |
Fred Hutchinson Cancer Center
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| Lab |
Prlic
|
| Street address |
1100 Fairview Ave, Mail stop E5-110
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| City |
Seattle |
| State/province |
WA |
| ZIP/Postal code |
98102 |
| Country |
USA |
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| Platforms (1) |
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| Samples (12)
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| This SubSeries is part of SuperSeries: |
| GSE246933 |
TGF-β broadly modifies rather than specifically suppresses reactivated memory CD8 T cells in a dose-dependent manner |
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| Relations |
| BioProject |
PRJNA1035122 |
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