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| Status |
Public on Jul 03, 2019 |
| Title |
Tox reinforces the phenotype and longevity of exhausted T-cells in chronic viral infection [ATAC-seq] |
| Organism |
Mus musculus |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
Chronic CD8 T-cell stimulation in persisting infections or tumors can induce a stable gene expression program, known as T-cell dysfunction or exhaustion, that limits the cell’s effector functions and anti-viral and anti-tumor immunity. Thus far, the underlaying molecular mechanisms that induce and stabilize this phenotype are vaguely understood. We report here that establishing this program requires the thymocyte selection-associated high mobility group-box protein (Tox). Genetic disruption of Tox augments effector function, decreases the expression of PD-1, and significantly enhances immunopathology. These changes are linked to a failure in fixing the dysfunctional phenotype in the critical Tcf1+ progenitor population and to impaired epigenetic programing. Surprisingly, the gains in effector function co-incide with declining numbers of Tcf1+ cells and result ultimately in reduced total numbers of pathogen-specific T-cells. Thus, we establish Tox as a critical factor for the development of T-cell dysfunction and establish a clear link between CD8 T-cell intrinsic suppression of effector function and protection against immune-pathology.
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| Overall design |
C57BL/6 mice engrafted with wt or Tox∆Ex5 2x10^3 P14 T-cells were infected with 2x10^6 PFU of LCMV clone-13. On day 8 post infection, splenic wt and Tox∆Ex5 P14 T-cells were sorted into Tim-3+ and Tim-3- T-cells and whole-genome DNA methylation analysis was performed as previously described (Ghoneim, et al. Cell 2017, PMID: 28648661). On day 8 and day 13 post infection, ATAC-seq was performed on splenic wt and Tox∆Ex5 P14 T-cells.
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| Contributor(s) |
Alfei F, Ghoneim HE, Fan Y, Youngblood B, Zehn D |
| Citation(s) |
31207605 |
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| Submission date |
May 22, 2019 |
| Last update date |
Jul 03, 2019 |
| Contact name |
yiping fan |
| E-mail(s) |
[email protected]
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| Phone |
9015955716
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| Organization name |
st jude children's hospital
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| Street address |
262 Danny Thomas Place
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| City |
memphis |
| State/province |
tn |
| ZIP/Postal code |
38105 |
| Country |
USA |
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| Platforms (1) |
| GPL21103 |
Illumina HiSeq 4000 (Mus musculus) |
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| Samples (4)
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| This SubSeries is part of SuperSeries: |
| GSE131643 |
Tox reinforces the phenotype and longevity of exhausted T-cells in chronic viral infection |
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| Relations |
| BioProject |
PRJNA544256 |
| SRA |
SRP199202 |
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