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| Status |
Public on Oct 19, 2021 |
| Title |
Transcriptional analysis of noncanonical and canonical Tregs from ITK deficient mice (ITK KO) |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Regulatory T cells (Tregs) play a critical role in controlling autoimmunity and limiting tissue destruction and inflammation. IL2-inducible T cell kinase (Itk) belongs to the Tec family of tyrosine kinases and is an important component of TCR-mediated signaling. Here we showed that either genetic ablation of Itk signaling, or inhibition of Itk signaling pathways resulted in increased frequency of “noncanonical” CD4+CD25−FoxP3+ Tregs (ncTregs), as well as of “canonical” CD4+CD25+FoxP3+ Tregs (canTregs). Using in vivo models, we showed that ncTregs can prevent the development of acute graft-versus-host disease (GVHD), in part by reducing conventional T cell proliferation, proinflammatory cytokine production, and tissue damage. This reduction in GVHD occurred without disruption of graft-versus-leukemia (GVL) effects. RNA sequencing revealed that a number of effector, cell adhesion, and migration molecules were upregulated in Itk-/- ncTregs. Furthermore, disrupting the SLP76: ITK interaction using a specific peptide inhibitor led to enhanced Treg development in both mouse cells and primary human cells. This peptide inhibitor also significantly reduced inflammatory cytokine production in primary GVHD patient samples and mouse T cells without causing cell death or apoptosis. We provide evidence that specifically targeting Itk signaling could be a therapeutic strategy to treat autoimmune disorders
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| Overall design |
We analyzed FACS purified canonical (CD25+, FOXP3+) and noncanonical (CD25-, FOXP3+) Tregs of 3 different ITK deficient (ITK KO) mice and canonical (CD25+, FOXP3+) Tregs of 3 different WT mouse.
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| Contributor(s) |
Mammadli M, Waickman A |
| Citation(s) |
34919342 |
| NIH grant(s) |
| Grant ID |
Grant title |
Affiliation |
Name |
| K22 AI130182 |
Novel strategies to separate GVHD from GVT |
SUNY Upstate Medical University |
MOBIN KARIMI |
|
| Submission date |
Oct 05, 2021 |
| Last update date |
Jan 10, 2022 |
| Contact name |
Mobin Karimi |
| E-mail(s) |
karimim@upstate.edu
|
| Phone |
3154642344
|
| Organization name |
Suny Upstate Medical University
|
| Department |
Microbiology/Immunology
|
| Lab |
Karimi
|
| Street address |
766 Irving Ave Suite 2281
|
| City |
Syracuse |
| State/province |
NY |
| ZIP/Postal code |
13210 |
| Country |
USA |
| |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (9)
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| Relations |
| BioProject |
PRJNA768766 |
| SRA |
SRP340076 |
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