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Mutations in STAT3 and IL12RB1 impair the development of human IL-17-producing T cells.

ABSTRACT: The cytokines controlling the development of human interleukin (IL) 17--producing T helper cells in vitro have been difficult to identify. We addressed the question of the development of human IL-17--producing T helper cells in vivo by quantifying the production and secretion of IL-17 by fresh T cells ex vivo, and by T cell blasts expanded in vitro from patients with particular genetic traits affecting transforming growth factor (TGF) beta, IL-1, IL-6, or IL-23 responses. Activating mutations in TGFB1, TGFBR1, and TGFBR2 (Camurati-Engelmann disease and Marfan-like syndromes) and loss-of-function mutations in IRAK4 and MYD88 (Mendelian predisposition to pyogenic bacterial infections) had no detectable impact. In contrast, dominant-negative mutations in STAT3 (autosomal-dominant hyperimmunoglobulin E syndrome) and, to a lesser extent, null mutations in IL12B and IL12RB1 (Mendelian susceptibility to mycobacterial diseases) impaired the development of IL-17--producing T cells. These data suggest that IL-12Rbeta1- and STAT-3--dependent signals play a key role in the differentiation and/or expansion of human IL-17-producing T cell populations in vivo.

SUBMITTER: de Beaucoudrey L

PROVIDER: S-EPMC2442631 | biostudies-literature | 2008 Jul

REPOSITORIES: biostudies-literature

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Mutations in STAT3 and IL12RB1 impair the development of human IL-17-producing T cells.

de Beaucoudrey Ludovic L Puel Anne A Filipe-Santos Orchidée O Cobat Aurélie A Ghandil Pegah P Chrabieh Maya M Feinberg Jacqueline J von Bernuth Horst H Samarina Arina A Jannière Lucile L Fieschi Claire C Stéphan Jean-Louis JL Boileau Catherine C Lyonnet Stanislas S Jondeau Guillaume G Cormier-Daire Valérie V Le Merrer Martine M Hoarau Cyrille C Lebranchu Yvon Y Lortholary Olivier O Chandesris Marie-Olivia MO Tron François F Gambineri Eleonora E Bianchi Lucia L Rodriguez-Gallego Carlos C Zitnik Simona E SE Vasconcelos Julia J Guedes Margarida M Vitor Artur Bonito AB Marodi Laszlo L Chapel Helen H Reid Brenda B Roifman Chaim C Nadal David D Reichenbach Janine J Caragol Isabel I Garty Ben-Zion BZ Dogu Figen F Camcioglu Yildiz Y Gülle Sanyie S Sanal Ozden O Fischer Alain A Abel Laurent L Stockinger Birgitta B Picard Capucine C Casanova Jean-Laurent JL

The Journal of experimental medicine 20080701 7

The cytokines controlling the development of human interleukin (IL) 17--producing T helper cells in vitro have been difficult to identify. We addressed the question of the development of human IL-17--producing T helper cells in vivo by quantifying the production and secretion of IL-17 by fresh T cells ex vivo, and by T cell blasts expanded in vitro from patients with particular genetic traits affecting transforming growth factor (TGF) beta, IL-1, IL-6, or IL-23 responses. Activating mutations in ...[more]

PMID: 18591412

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Project description:The immunomodulatory and self-renewable features of human adipose mesenchymal stem cells (hAD-MSCs) mark their importance in regenerative medicine. Interleukin 23 (IL- 23) as a proinflammatory cytokine suppresses T regulatory cells (Treg) and promotes the response of T helper 17 (Th17) and T helper 1 (Th1) cells. This pathway starts inflammation and immunosuppression in several autoimmune diseases. The current study for producing recombinant IL- 23 decoy receptor (RIL- 23R) using hAD-MSCs as a good candidate for ex vivo cell-based gene therapy purposes reducing inflammation in autoimmune diseases. hAD-MSCs was isolated from lipoaspirate and then characterized by differentiation. RIL- 23R was designed and cloned into a pCDH-813A- 1 lentiviral vector. The transduction of hAD-MSCs was performed at MOI (multiplicity of infection) = 50 with pCDH- EFI ?- RIL- 23R- PGK copGFP. Expressions of RIL- 23R and octamer-binding transcription factor 4 (OCT- 4) were determined by real-time polymerase chain reaction (real time-PCR). Self-renewing properties were assayed with OCT- 4. Bioactivity of the designed RIL- 23R was evaluated by IL- 17 and IL- 10 expression of mouse splenocytes. Cell differentiation confirmed the true isolation of hAD-MSCs from lipoaspirate. Restriction of the enzyme digestion and sequencing verified the successful cloning of RIL- 23R in the CD813A-1 lentiviral vector. The green fluorescent protein (GFP) positive transduction rate was up to 90%, and real-time PCR showed the expression level of RIL-23R. Oct-4 had a similar expression pattern with nontransduced hAD-MSCs and transduced hAD-MSCs/ RIL-23R indicating that lentiviral vector did not affect hAD-MSCs characteristics. Downregulation of IL-17 and upregulation of IL-10 showed the correct activity of the engineered hAD-MSCs. The results showed that the transduced hAD-MSCs/ RIL- 23R, expressing IL-23 decoy receptor, can give a useful approach for a basic research on cell-based gene therapy for autoimmune disorders.

Dataset Information

Mutations in STAT3 and IL12RB1 impair the development of human IL-17-producing T cells.

Publications

Mutations in STAT3 and IL12RB1 impair the development of human IL-17-producing T cells.

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