IL-10/Janus kinase/signal transducer and activator of transcription 3 signaling dysregulates Bim expression in autoimmune lymphoproliferative syndrome - 05/03/15
Abstract |
Background |
Autoimmune lymphoproliferative syndrome (ALPS) is a human disorder of T cell homeostasis caused by mutations that impair FAS-mediated apoptosis. A defining characteristic of ALPS is the expansion of double negative T cells (DNTC). Relatively little is known about how defective FAS-driven cell death and the Bcl-2 apoptotic pathway intersect in ALPS patients.
Objective |
We studied changes in Bcl-2 family member expression in ALPS to determine whether the Bcl-2 pathway might provide a therapeutic target.
Methods |
We used flow cytometry to analyze the expression of pro- and anti-apoptotic Bcl-2 family members in T cells from 12 ALPS patients and determined the in vitro sensitivity of ALPS DNTC to the pro-apoptotic BH3 mimetic, ABT-737.
Results |
The pro-apoptotic molecule, Bim, was significantly elevated in DNTC. Although no general pattern of individual anti-apoptotic Bcl-2 family members emerged, increased expression of Bim was always accompanied by increased expression of at least 1 anti-apoptotic Bcl-2 family member. Strikingly, Bim levels in DNTC correlated significantly with serum IL-10 in ALPS patients, and IL-10 was sufficient to mildly induce Bim in normal and ALPS T cells via a Janus kinase/signal transducer and activator of transcription 3–dependent mechanism. Finally, ABT-737 preferentially killed ALPS DNTC in vitro.
Conclusion |
Combined, these data show that an IL-10/Janus kinase/signal transducer and activator of transcription 3 pathway drives Bim expression in ALPS DNTC, which renders them sensitive to BH3 mimetics, uncovering a potentially novel therapeutic approach to ALPS.
Le texte complet de cet article est disponible en PDF.Key words : ALPS, Bim, Bcl-2 pathway, IL-10, BH3 mimetic, ABT-737, T cell homeostasis, double negative T cells, apoptosis
Abbreviations used : ALPS, CDR, DNTC, IL-10R, Jak, lpr, MFI, NF-κB, STAT, TCR
Plan
| This project was supported by a grant from the Primary Immune Deficiency Treatment Consortium (a subaward from NIH/NIAID grant U54 AI082973), the United States National Institutes of Health (NIH) grants AI057753 and DK081175 (to D.A.H.), and by NIH grants AR 47363 and P30 DK078392 (of the Digestive Research Core Center at Cincinnati Children's Hospital) which support the research flow cytometry core. |
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| Disclosure of potential conflict of interest: O. Niss and D. Hildeman have received research support from the Primary Immune Deficiency Treatment Consortium and are employed at Cincinnati Children's Hospital Medical Center. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 135 - N° 3
P. 762-770 - mars 2015 Retour au numéro
Article précédent
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