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| Status |
Public on Jul 25, 2016 |
| Title |
A Pro-Asthmatic IL-4 Receptor Allele Promotes Airway Inflammation by Programming TH17 Cell-Like Regulatory T cells |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Mechanisms by which regulatory T (Treg) cells fail to control inflammation in asthma remain poorly understood. We show that a severe asthma-associated polymorphism in the interleukin-4 receptor alpha chain (IL-4Rα-R576) biases induced Treg (iTreg) cells towards a T helper 17 (TH17) cell fate. This skewing reflects the recruitment by IL-4Rα-R576 of the adaptor protein growth factor receptor-bound protein 2 (GRB2), which drives IL-17 expression by an extracellular signal-regulated kinase-, IL-6- and STAT3-dependent mechanism. We showed that the IL-4Rα-R576 mutation elicits TH17 airway responses in vivo, in a house dust mite (HDM)- or ovalbumin (OVA)-driven model of airway inflammation in the mice carry the IL-4Rα-R576 mutation (Il4raR576 mice). Treg cell-specific deletion of genes encoding IL-6Rα or the master TH17 cell regulator Retinoid-related Orphan Receptor γt (RORγt), but not IL-4 and IL-13, protected mice against exacerbated airway inflammation induced by IL-4Rα--576. Analysis of lung tissue Treg cells revealed that the expression of IL-17 and the TH17 cell-associated chemokine receptor CCR6 was largely overlapping and highly enriched in Treg and conventional T (Tconv) cells of allergen-treated Il4raR576 mice. To further characterize the subset of IL-17 producing Foxp3+ Treg in the lung of OVA-treated mice we utilized CCR6 as a marker of Treg cells committed towards the TH17 cell lineage to examine their functional, epigenetic and transcriptional profiles. CCR6+Foxp3EGFP+ Treg cells isolated from OVA-sensitized and challenged Il4raR576 mice, by FACS (Fluorescence Activated Cell Sorting) exhibited decreased methylation of the Foxp3 CNS2 locus comparing to CCR6–Foxp3EGFP+ Treg cells from same animals, indicative of decreased stability. They also exhibited profoundly decreased suppressive function as compared to CCR6– WT and CCR6– Il4raR576 counterparts. Transcriptional profiling of CCR6+Foxp3EGFP+ Treg cells revealed increased relative expression in CCR6+ Il4raR576 Treg cells of genes associated with a TH17 cell signature, including Rorc, Ccr6, Il23r, Il17a, Il17f, Il1r1, Nr1d1, Cstl, and Ahr comparing to CCR6–Foxp3EGFP+ Treg cells from same animals.
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| Overall design |
Three CCR6+Foxp3EGFP+ Il4raR576 replicates and four CCR6–Foxp3EGFP+ Il4raR576 Treg replicates (controls) were sampled
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| Contributor(s) |
Massoud AH, Charbonnier L, Lopez D, Pellegrini M, Phipatanakul W, Chatila T |
| Citation(s) |
27479084 |
| Submission date |
Apr 28, 2016 |
| Last update date |
May 15, 2019 |
| Contact name |
Matteo Pellegrini |
| E-mail(s) |
matteop@mcdb.ucla.edu
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| Phone |
310-825-0012
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| Organization name |
UCLA
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| Street address |
610 Charles Young Drive East
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| City |
Los Angeles |
| State/province |
CA |
| ZIP/Postal code |
90095 |
| Country |
USA |
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| Platforms (1) |
| GPL21493 |
Illumina HiSeq 3000 (Mus musculus) |
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| Samples (7)
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| Relations |
| BioProject |
PRJNA320002 |
| SRA |
SRP074156 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE80804_RAW.tar |
1.0 Mb |
(http)(custom) |
TAR (of TXT) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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