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| Status |
Public on Apr 08, 2022 |
| Title |
Autoreactive CD8+ T cells are restrained by an exhaustion-like program that is maintained by LAG3 |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
CD8+ T cell exhaustion is a distinct differentation state resulting from chronic antigen exposure and leading to hierarchical loss of effector functions. Using a murine model of diabetes, we show that CD8+ T cells derived from the islets of diabetic mice have CD8+ T cells that are canonically exhausted and yet retain sufficient effector function to contribute to pathogenicity in autoimmune diabetes. Genetic deletion of the inhibitory receptor LAG3 restricted to only CD8+ T cells lead to accelerated disease, with LAG3 deficient CD8+ T cells having enhanced effector function and trafficking. These findings reveal a distinct role of LAG3 in restraining autoreactive CD8+ T cells and implicate LAG3 as a potential therapeutic target in autoimmunity.
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| Overall design |
NOD mice harboring a CD8+ T cell restricted genetic deletion of LAG3 were used to assess the role of LAG3 in autoimmune diabetes and were compared to control mice. CD8+ T cells were isolated from islets and lymph nodes by FACS. Bulk RNAseq, single-cell RNAseq with paired TCRseq, and single-cell ATACseq were performed on these isolated CD8+ T cells from control and LAG3 deleted mice. CD8+ T cells from three eight-week old female mice per group were pooled across two independent experiments for bulk RNAseq. CD8+ T cells from four eight-week old mice per group were used for scRNAseq experiments. CD8+ T cells from four eight-week old mice were used for scATACseq experiments.
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| Contributor(s) |
Cillo AR, Grebinowski S, Vignali DA |
| Citation(s) |
35618829 |
| NIH grant(s) |
| Grant ID |
Grant title |
Affiliation |
Name |
| R01 DK089125 |
Parameters that Underlie Treg Insufficiency in Autoimmune Diabetes |
UNIVERSITY OF PITTSBURGH AT PITTSBURGH |
Dario AA Vignali |
| R01 AI144422 |
Structure, Function and Mechanistic Analysis of LAG3 |
UNIVERSITY OF PITTSBURGH AT PITTSBURGH |
Dario AA Vignali |
| R01 AI144422 |
Structure, Function and Mechanistic Analysis of LAG3 |
UNIVERSITY OF PITTSBURGH AT PITTSBURGH |
CREG J WORKMAN |
| P01 AI108545 |
Synergies among inhibitory receptors in tolerance, cancer & antiviral immunity |
UNIVERSITY OF PITTSBURGH AT PITTSBURGH |
Dario AA Vignali |
| F31 AI147638 |
Investigating a disintegrin and metalloproteinase-mediated Neuropilin 1 cleavage in autoimmune diabetes |
UNIVERSITY OF PITTSBURGH AT PITTSBURGH |
Stephanie Grebinoski |
| T32 AI089443 |
Autoimmunity and Immunopathology Training Program |
UNIVERSITY OF PITTSBURGH AT PITTSBURGH |
MARK J SHLOMCHIK |
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| Submission date |
Mar 24, 2022 |
| Last update date |
Jul 08, 2022 |
| Contact name |
Anthony Richard Cillo |
| E-mail(s) |
arc85@pitt.edu
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| Organization name |
University of Pittsburgh
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| Department |
Immunology
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| Street address |
The Assembly, Room 4070C Bay 10, 5051 Centre Ave
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| City |
Pittsburgh |
| State/province |
PA |
| ZIP/Postal code |
15213 |
| Country |
USA |
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| Platforms (2) |
| GPL21626 |
NextSeq 550 (Mus musculus) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (23)
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| Relations |
| BioProject |
PRJNA819445 |
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