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Status |
Public on Oct 18, 2022 |
Title |
Pre-T cell receptor Self-MHC Sampling Restricts Thymocyte Dedifferentiation |
Organism |
Mus musculus |
Experiment type |
Expression profiling by high throughput sequencing Other
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Summary |
Programming T lymphocytes to distinguish self from non-self is a vital, multi-step process arising in the thymus. Signalling through the pre-T cell receptor (preTCR), a CD3-associated heterodimer comprising an invariant pTα chain and a clone-specific β chain, constitutes a critical early checkpoint in thymocyte development within the αβ T-cell lineage. Recent work demonstrates that preTCRs arrayed on double negative (DN) thymocytes, like αβ TCRs appearing on double positive (DP) thymocytes, ligate peptides bound to MHC molecules (pMHC) on thymic stroma but via a different molecular docking strategy. Here we show the consequences of those distinctive interactions for thymocyte progression, using synchronized fetal thymic progenitor cultures differing in the presence or absence of pMHC on support stroma, determining single cell transcriptomes at key thymocyte developmental transitions. Although MHC negative stroma fosters αβ T lymphocyte differentiation, the absence of pMHC-preTCR interplay leads to deviant thymocyte transcriptional programming associated with de-differentiation. Highly proliferative DN and DP subsets with antecedent characteristics of T cell lymphoblastic and myeloid malignancies emerge. Thus, in addition to fostering β chain repertoire broadening for subsequent αβ TCR utilization, preTCR-pMHC interaction limits cellular plasticity to facilitate normal thymocyte differentiation and proliferation that, if absent, introduces significant developmental vulnerabilities.
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Overall design |
Transcriptional profiling of early thymocytes developing in the presence or absence of peptide-MHC
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Contributor(s) |
Duke-Cohan JS, Akitsu A, Mallis RJ, Messier CM, Lizotte PH, Hwang W, Lang MJ, Reinherz EL |
Citation(s) |
36410718 |
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Submission date |
Oct 18, 2021 |
Last update date |
Jan 17, 2023 |
Contact name |
Jonathan S. Duke-Cohan |
E-mail(s) |
Jonathan_Duke-Cohan@dfci.harvard.edu
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Phone |
+1-617-632-3122
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Organization name |
Dana-Farber Cancer Institute
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Department |
Medical Oncology
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Lab |
Immunobiology
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Street address |
450 Brookline Avenue JF517
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City |
Boston |
State/province |
MA |
ZIP/Postal code |
02215 |
Country |
USA |
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Platforms (1) |
GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
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Samples (18)
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GSM5629779 |
MHC+ DN3a transcripts (file prefix: PDN3a_) |
GSM5629780 |
MHC+ DN3b transcripts (file prefix: PDN3b_) |
GSM5629781 |
MHC+ DN4 transcripts (file prefix: PDN4_) |
GSM5629782 |
MHC+ DP transcripts (file prefix: PDP_) |
GSM5629783 |
MHC- DN3a transcripts (file prefix: NDN3a_) |
GSM5629784 |
MHC- DN3b transcripts (file prefix: NDN3b_) |
GSM5629785 |
MHC- DN4 transcripts (file prefix: NDN4_) |
GSM5629786 |
MHC- DP transcripts (file prefix: NDP_) |
GSM5629787 |
OP9-DL4 transcripts |
GSM5629788 |
OP9-DL4 Class I knockout transcripts |
GSM5629789 |
MHC+ DN3a TCR transcripts (file prefix: PDN3a_TCR_) |
GSM5629790 |
MHC+ DN3b TCR transcripts (file prefix: PDN3b_TCR_) |
GSM5629791 |
MHC+ DN4 TCR transcripts (file prefix: PDN4_TCR_) |
GSM5629792 |
MHC+ DP TCR transcripts (file prefix: PDP_TCR_) |
GSM5629793 |
MHC- DN3a TCR transcripts (file prefix: NDN3a_TCR_) |
GSM5629794 |
MHC- DN3b TCR transcripts (file prefix: NDN3b_TCR_) |
GSM5629795 |
MHC- DN4 TCR transcripts (file prefix: NDN4_TCR_) |
GSM5629796 |
MHC- DP TCR transcripts (file prefix: NDP_TCR_) |
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Relations |
BioProject |
PRJNA772188 |
SRA |
SRP341932 |
Supplementary file |
Size |
Download |
File type/resource |
GSE186049_2021-09-02-Duke-Cohan-File-1-MHCpos-GEX-all-libraries-all-clusters.xlsx |
19.1 Mb |
(ftp)(http) |
XLSX |
GSE186049_2021-09-02-Duke-Cohan-File-2-MHCneg-GEX-all-libraries-all-clusters.xlsx |
19.6 Mb |
(ftp)(http) |
XLSX |
GSE186049_2021-09-02-Duke-Cohan-File-3-OP9-DL4-MHCpos-MHCneg.xlsx |
5.0 Mb |
(ftp)(http) |
XLSX |
GSE186049_RAW.tar |
527.7 Mb |
(http)(custom) |
TAR (of CSV, MTX, TSV) |
SRA Run Selector |
Raw data are available in SRA |
Processed data provided as supplementary file |
Processed data are available on Series record |
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