Conditional Deletion of Histone Deacetylase 1 in T Cells Leads to Enhanced Airway Inflammation and Increased Th2 Cytokine Production.
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Grausenburger, Reinhard, Bilic, Ivan, Boucheron, Nicole, Zupkovitz, Gordin, El-Housseiny, Lamia, Tschismarov, Roland, Zhang, Yu, Rembold, Martina, Gaisberger, Martin, Hartl, Arnulf, Epstein, Michelle M, Matthias, Patrick, Seiser, Christian and Ellmeier, Wilfried (2010) Conditional Deletion of Histone Deacetylase 1 in T Cells Leads to Enhanced Airway Inflammation and Increased Th2 Cytokine Production. The Journal of Immunology (Baltimore, Md. : 1950), 185 (6). pp. 3489-3497. ISSN 1550-6606
Abstract
Chromatin modifications, such as reversible histone acetylation, play a key role in the regulation of T cell development and function. However, the role of individual histone deacetylases (HDACs) in T cells is less well understood. In this article, we show by conditional gene targeting that T cell-specific loss of HDAC1 led to an increased inflammatory response in an in vivo allergic airway inflammation model. Mice with HDAC1-deficient T cells displayed an increase in all critical parameters in this Th2-type asthma model, such as eosinophil recruitment into the lung, mucus hypersecretion, parenchymal lung inflammation, and enhanced airway resistance. This correlated with enhanced Th2 cytokine production in HDAC1-deficient T cells isolated from diseased mice. In vitro-polarized HDAC1-deficient Th2 cells showed a similar enhancement of IL-4 expression, which was evident already at day 3 of Th2 differentiation cultures and restricted to T cell subsets that underwent several rounds of cell divisions. HDAC1 was recruited to the Il4 gene locus in ex vivo isolated nonstimulated CD4(+) T cells, indicating a direct control of the Il4 gene locus. Our data provide genetic evidence that HDAC1 is an essential HDAC that controls the magnitude of an inflammatory response by modulating cytokine expression in effector T cells.
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| Date Deposited: | 02 Nov 2010 00:45 |
| Last Modified: | 01 Feb 2013 00:48 |
| URI: | https://oak.novartis.com/id/eprint/3895 |