Research Papers: Immunology:

Expression of non-secreted IL-4 is associated with HDAC inhibitor-induced cell death, histone acetylation and c-Jun regulation in human gamma/delta T-cells

Jaydeep Bhat, Justyna Sosna, Jürgen Fritsch, Elgar Susanne Quabius, Stefan Schütze, Sebastian Zeissig, Ole Ammerpohl, Dieter Adam and Dieter Kabelitz _

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Oncotarget. 2016; 7:64743-64756. https://doi.org/10.18632/oncotarget.11462

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Jaydeep Bhat1,**, Justyna Sosna1,5,*, Jürgen Fritsch1,*, Elgar Susanne Quabius1,2,*, Stefan Schütze1, Sebastian Zeissig3,6,7, Ole Ammerpohl4, Dieter Adam1 and Dieter Kabelitz1

1 Institute of Immunology, Christian-Albrechts-University, Kiel, Germany

2 Department of Otorhinolaryngology, Head and Neck Surgery, Christian-Albrechts-University, Kiel, Germany

3 Department of Internal Medicine I, Christian-Albrechts-University, Kiel, Germany

4 Institute of Human Genetics, University Medical Center Schleswig-Holstein Kiel, Christian-Albrechts-University, Kiel, Germany

5 Current address: Department of Molecular Biology and Biochemistry, University of California-Irvine, Irvine, CA, USA

6 Current address: Department of Medicine I, University Medical Center Dresden, Technical University Dresden, Dresden, Germany

7 Current address: Center for Regenerative Therapies Dresden (CRTD), Technical University Dresden, Dresden, Germany

* Authors contributed equally

** This work forms part of the Ph.D. thesis of J.B.

Correspondence to:

Dieter Kabelitz, email:

Keywords: IL-4, apoptosis, necroptosis, HDAC inhibitors, valproic acid, Immunology and Microbiology Section, Immune response, Immunity

Received: May 11, 2016 Accepted: August 11, 2016 Published: August 20, 2016


Previously, the expression of a non-secreted IL-4 variant (IL-4δ13) has been described in association with apoptosis and age-dependent Th2 T-cell polarization. Signaling pathways involved in this process have so far not been studied. Here we report the induction of IL-4δ13 expression in human γδ T-cells upon treatment with a sublethal dose of histone deacetylase (HDACi) inhibitor valproic acid (VPA). Induction of IL-4δ13 was associated with increased cytoplasmic IL-4Rα and decreased IL-4 expression, while mRNA for mature IL-4 was concomitantly down-regulated. Importantly, only the simultaneous combination of apoptosis and necroptosis inhibitors prevented IL-4δ13 expression and completely abrogated VPA-induced global histone H3K9 acetylation mark. Further, our work reveals a novel involvement of transcription factor c-Jun in the signaling network of IL-4, HDAC1, caspase-3 and mixed lineage kinase domain-like protein (MLKL). This study provides novel insights into the effects of epigenetic modulator VPA on human γδ T-cell differentiation.

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