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| Status |
Public on Sep 05, 2023 |
| Title |
Targeting pathogenic CD8+ tissue-resident T cells with chimeric antigen receptor therapy in murine autoimmune cholangitis |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Primary biliary cholangitis (PBC) is a cholestatic autoimmune liver disease secondary to an autoreactive T cell response against intrahepatic small bile ducts. Multiple murine models have demonstrated the critical role of effector CD8+T cells in this response and our work has used IL-12p40-/-IL-2Rα-/- mice (DKO mice) to study this issue. Herein we first demonstrated that use of either a CD8a knock-out or an anti-CD8a antibody prevents/reduces biliary immunopathology. Bulk and single-cell RNA sequencing analysis identifies CD8+ tissue resident memory T cells (Trm) in the liver of DKO mice, which highly express activation and cytotoxicity associated markers and have the ability to induce apoptosis of bile duct epithelial cells. Liver CD8+Trm cells also upregulate expression of several immune checkpoint molecules and in particular we identified PD-1 as a specific liver CD8+Trm cell marker in this model. Based on these data we constructed a novel chimeric antigen receptor containing a PD-L1 extracellular domain to target PD-1-expressing CD8+Trm cells. Importantly, treatment of DKO mice with PD-1 targeting CAR-T cells selectively depleted liver CD8+Trm cells in vivo and alleviated autoimmune cholangitis.
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| Overall design |
To access the efficacy of anti-PD-1 CAR-T treatment, we extracted the total RNA of liver tissues of DKO mice after anti-PD-1 CAR-T or Ctrl-T infusion and their control littermates, , then we build the cDNA library and performed the bulk RNA sequencing.
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| Contributor(s) |
Hao-Xian Z, Shu-Han Y |
| Citation(s) |
38580644 |
| |
| Submission date |
Aug 16, 2023 |
| Last update date |
Apr 24, 2024 |
| Contact name |
Hao-Xian ZHU |
| E-mail(s) |
zhuhx97@gmail.com
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| Organization name |
Guangdong Provincial People’s Hospital
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| Street address |
No. 106, Zhongshan 2nd Road
|
| City |
guangzhou |
| State/province |
Guangdong |
| ZIP/Postal code |
510000 |
| Country |
China |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (17)
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| Relations |
| BioProject |
PRJNA1006041 |
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