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| Status |
Public on Oct 06, 2018 |
| Title |
Specific targeting of the common gamma chain blocks cooperative reprogramming of human tissue-resident cytotoxic T lymphocytes by IL-15 and IL-21 |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
The common gamma chain (γc) is required for productive signaling by interleukin (IL)-15, IL-21 and IL-2, which are critically involved in immune activation and regulation. IL-21 and IL-15 are implicated in the pathogenesis of type-1 diabetes, graft-versus-host disease, and celiac disease (CeD), a gluten-mediated autoimmune-like enteropathy. Attempts to treat type-1 diabetes and graft-versus-host disease with biologics targeting one particular cytokine have failed. Both IL-15 and IL-21 have been suggested to drive activation of cytotoxic T cells (CTL) that are the effectors mediating tissue destruction in CeD and organ-specific autoimmune disorders. We show that the concomitant upregulation of IL-15 and IL-21 occurs only in full-blown CeD with villous atrophy. BNZ-2, a peptide that targets the γc, was able to block the cooperative IL-15/IL-21 mediated transcriptional activation of human tissue-resident intraepithelial CTL. Importantly, this inhibition was specific and did not interfere with IL-2 signaling, a cytokine with known immunoregulatory functions. Moreover, BNZ-2 blocked gluten-induced IFN-γ production in small intestinal organ cultures from CeD patients. These observations identify BNZ-2 as a therapeutic candidate for immune disorders in which IL-15 and IL-21 cooperate to induce CTL-mediated tissue damage.
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| Overall design |
Gene expression profiles of human tissue-resident IE-CTLs (both in vitro and ex vivo), before and after simulation with IL-15 and IL-21 (individually and in combination).
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| Contributor(s) |
Cezary C, Valentina D, Alain P, Nick D, Mariantonia M, Asjad B, Laith A, Riccardo T, Nazli A, Yutaka T, Luis B, Bana J |
| Citation(s) |
31622625 |
| Submission date |
Oct 05, 2018 |
| Last update date |
Jan 08, 2020 |
| Contact name |
Alain Pacis |
| E-mail(s) |
alain.pacis@mcgill.ca
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| Organization name |
Canadian Centre for Computational Genomics (C3G)
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| Street address |
740 Dr Penfield Ave
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| City |
Montreal |
| State/province |
QC |
| ZIP/Postal code |
H3A 0G1 |
| Country |
Canada |
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| Platforms (1) |
| GPL20301 |
Illumina HiSeq 4000 (Homo sapiens) |
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| Samples (87)
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| Relations |
| BioProject |
PRJNA494882 |
| SRA |
SRP163900 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE120904_RAW.tar |
16.4 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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