 |
 |
GEO help: Mouse over screen elements for information. |
|
| Status |
Public on Nov 10, 2022 |
| Title |
The transcription factor IRF2 drives interferon-mediated CD8+ T cell exhaustion to restrict anti-tumor immunity |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
|
| Summary |
Type I Interferons (IFN-I) stimulate pro-inflammatory programs critical for immune activation, but also induce immune-suppressive feedback circuits that contribute to the failure of cancer control. Yet, how IFN-Is differentially induce these opposing programs remains enigmatic. We establish that the transcription factor Interferon Regulatory Factor 2 (IRF2) is a central feedback molecule attenuating IFN signaling and driving CD8 T cell exhaustion in the tumor microenvironment. IRF2 inhibits CD8 T cell effector function in response to sustained interferon signaling by programming T cell exhaustion. Lineage-specific deletion of IRF2 limits CD8 T cells exhaustion to maintain effector functions, thereby enabling long-term tumor control, and increased responsiveness to immune-checkpoint and adoptive cell therapies. Long-term tumor control by IRF2-deficient CD8 T cells is dependent on continuous integration of both IFN-I and IFN? signals, which in the absence of IRF2, potentiate sustained effector function instead of exhaustion. Thus, IRF2 redirects IFN signalling to drive T cell exhaustion and prevent tumor control.
|
| |
|
| Overall design |
For AB-Seq experiment, MC38 Tumor-infitrating CD8 T cells from WT (Tumor WT), Irf2-/- (Tumor IRF2KO) mice. For scATAC-Seq experiment, MC38 Tumor-infitrating CD8 T cells from WT (Tumor WT), Irf2-/- (Tumor Irf2-/-) mice, as well as MC38 Tumor-infitrating CD8 T cells from mice that only lack IRF2 expression in the CD8 T cells (termed Tumor CD8-IRF2cKO mice) together with their controls Tumor CD8-IRF2cWT). For CUT&Tag - Naive isolated CD8+ T cells were isolated and invitro activated using anti-CD3 and Anti-CD28 and subjecte to either anti-IRF2 or IgG antibodies.
|
| Web link |
https://pubmed.ncbi.nlm.nih.gov/36370712/
|
| |
|
| Contributor(s) |
Lukhele S, Abd Rabbo D, Guo M, Shen J, Elsaesser HJ, Carew M, Gadalla R, Quevedo R, Snell LM, Ciudad TM, Snow BE, You-Ten A, Haight J, Wakeham A, Ohashi PS, Mak TW, Cui W, McGaha TL, Brooks DG |
| Citation(s) |
36370712 |
| |
| Submission date |
Mar 22, 2022 |
| Last update date |
Nov 16, 2022 |
| Contact name |
David Brooks |
| Organization name |
Princess Margaret Cancer Centre
|
| Street address |
610, University Ave
|
| City |
Toronto |
| ZIP/Postal code |
M5G 2C1 |
| Country |
Canada |
| |
|
| Platforms (2) |
| GPL21626 |
NextSeq 550 (Mus musculus) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
|
| Samples (8)
|
|
| Relations |
| BioProject |
PRJNA818703 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE199177_RAW.tar |
2.7 Gb |
(http)(custom) |
TAR (of TAR) |
| GSE199177_WT_n_IRF2.KO_CD8_T_cells.h5Seurat |
27.0 Mb |
(ftp)(http) |
H5SEURAT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
|
|
|
|
 |
Less...
More...