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| Status |
Public on Sep 29, 2022 |
| Title |
Inhibition of FOXP3 by Stapled Alpha-Helical Peptides Dampens Regulatory T Cell Function |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Despite continuing advances in the development of novel cellular-, antibody-, and chemotherapeutic-based strategies to enhance immune reactivity, the presence of regulatory T cells (Tregs) remains a complicating factor to their clinical efficacy. To overcome dosing limitations and off-target effects from antibody-based Treg deletional strategies, we investigated the ability of hydrocarbon stapled alpha-helical (SAH) peptides to target FOXP3, the master transcription factor regulator of Treg development, maintenance, and suppressive function. Using the crystal structure of the FOXP3 homodimer as a guide, we developed SAHs in the likeness of a portion of the native FOXP3 antiparallel coiled-coil homodimerization domain (SAH-FOXP3) to block this key FOXP3 protein-protein interaction (PPI) through molecular mimicry. We show that lead SAH-FOXP3s bind FOXP3, are cell permeable, non-toxic to T cells, induce dose-dependent transcript and protein level alterations of FOXP3 target genes, impede Treg function, and lead to Treg gene expression changes in vivo consistent with Foxp3 dysfunction.
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| Overall design |
Comparative gene expression profiling analysis of RNA-seq data for naïve CD4+ Tcons and CD4+CD25+FOXP3+ Tregs following 2 days of daily treatment with either SAH(229-259)C or vehicle. There are 12 samples total (6 Tcon samples, 6 Treg samples). Within each set of 6 Tcon or Treg samples, there are 2 vehicle-treated controls and 4 SAH-treated controls representing cells from either the lymph nodes or spleen.
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| Contributor(s) |
LaBelle J |
| Citation(s) |
36227917 |
| |
| Submission date |
Apr 20, 2022 |
| Last update date |
Oct 28, 2022 |
| Contact name |
James LaBelle |
| E-mail(s) |
jlabelle@bsd.uchicago.edu
|
| Organization name |
University of Chicago
|
| Street address |
900 East 57th Street, KCBD 5122
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| City |
Chicago |
| State/province |
IL |
| ZIP/Postal code |
60637 |
| Country |
USA |
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| Platforms (1) |
| GPL21103 |
Illumina HiSeq 4000 (Mus musculus) |
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| Samples (12)
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| Relations |
| BioProject |
PRJNA828456 |
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