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| Status |
Public on May 31, 2023 |
| Title |
PD-1 prevents pathogenicity of effector CD8 T cells that infiltrate skin under homeostatic conditions |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Self-reactive T cells are part of the peripheral T cell repertoire in healthy individuals. Checkpoint receptors like PD-1 allow the establishment of peripheral tolerance by inducing deletion or anergy of self-reactive CD8 T cells, however the high frequency of immune-related Adverse Events (irAEs) among cancer patients receiving checkpoint receptor inhibitor (CPI) immunotherapy led us to question how checkpoint receptors are involved in peripheral T cell tolerance. We developed a novel mouse model for studying peripheral T cell tolerance in the skin where skin-specific expression of T cell antigens (Ags) caused local infiltration of Ag-specific CD8 T cells with effector capacity. In this setting, PD-1 was required for maintaining local tolerance by allowing the co-existence of Ag-expressing cells and Ag-specific effector CD8 T cells in skin without tissue pathology, while CD8 T cell-mediated elimination of Ag-expressing cells and consequent tissue pathology developed in the absence of PD-1-mediated regulation. In this model, PD-1 allowed maintenance of skin tolerance by preventing tissue-infiltrating Ag-specific effector CD8 T cells from 1) acquiring a fully functional, pathogenic differentiation state, 2) secreting significant amounts of effector molecules, and 3) gaining access to Ag-expressing cells in the epidermis. Transcriptomic analysis of skin biopsies from two patients with cutaneous lichenoid irAEs showed presence of clonally expanded effector CD8 T cells in both lesional and non-lesional skin. Thus, our data support a model of peripheral T cell tolerance where PD-1 allows Ag-specific effector CD8 T cells to persist in a tissue where their cognate Ag is expressed without causing pathology.
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| Overall design |
Skin biopsies from patients with lichenoid cutaneous immune-related adverse events (lesional skin LS1-2, nonlesional skin NLS1-2) and healthy control patients (NS1-2) were analyzed using single-cell RNA sequencing on the 10X Genomics platform.
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| Contributor(s) |
Hornick NI, Damo M, Joshi NS |
| Citation(s) |
37344588 |
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| Submission date |
Apr 10, 2023 |
| Last update date |
Jun 29, 2023 |
| Contact name |
Nikhil Joshi |
| Organization name |
Yale University
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| Department |
Immunobiology
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| Street address |
300 Cedar St, PO Box 208011
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| City |
New Haven |
| State/province |
CT |
| ZIP/Postal code |
06520-8011 |
| Country |
USA |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (12)
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| GSM7157922 |
Healthy control skin patient 1, transcriptome |
| GSM7157923 |
Healthy control skin patient 1, TCR |
| GSM7157924 |
Healthy control skin patient 2, transcriptome |
| GSM7157925 |
Healthy control skin patient 2, TCR |
| GSM7157926 |
Nonlesional lichenoid irAE patient 1, transcriptome |
| GSM7157927 |
Nonlesional lichenoid irAE patient 1, TCR |
| GSM7157928 |
Nonlesional lichenoid irAE patient 2, transcriptome |
| GSM7157929 |
Nonlesional lichenoid irAE patient 2, TCR |
| GSM7157930 |
Lesional lichenoid irAE patient 1, transcriptome |
| GSM7157931 |
Lesional lichenoid irAE patient 1, TCR |
| GSM7157932 |
Lesional lichenoid irAE patient 2, transcriptome |
| GSM7157933 |
Lesional lichenoid irAE patient 2, TCR |
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| Relations |
| BioProject |
PRJNA953949 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE229279_RAW.tar |
81.8 Mb |
(http)(custom) |
TAR (of CSV, H5) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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