An epigenetic silencing pathway controlling T helper 2 cell lineage commitment

Abstract

During immune responses, naive CD4 + T cells differentiate into several T helper (T H) cell subsets under the control of lineage-specifying genes. These subsets (T H1, T H2 and T H17 cells and regulatory T cells) secrete distinct cytokines and are involved in protection against different types of infection. Epigenetic mechanisms are involved in the regulation of these developmental programs, and correlations have been drawn between the levels of particular epigenetic marks and the activity or silencing of specifying genes during differentiation. Nevertheless, the functional relevance of the epigenetic pathways involved in T H cell subset differentiation and commitment is still unclear. Here we explore the role of the SUV39H1-H3K9me3-HP1α silencing pathway in the control of T H2 lineage stability. This pathway involves the histone methylase SUV39H1, which participates in the trimethylation of histone H3 on lysine 9 (H3K9me3), a modification that provides binding sites for heterochromatin protein 1α (HP1α) and promotes transcriptional silencing. This pathway was initially associated with heterochromatin formation and maintenance but can also contribute to the regulation of euchromatic genes. We now propose that the SUV39H1-H3K9me3-HP1α pathway participates in maintaining the silencing of T H1 loci, ensuring T H2 lineage stability. In T H2 cells that are deficient in SUV39H1, the ratio between trimethylated and acetylated H3K9 is impaired, and the binding of HP1α at the promoters of silenced T H1 genes is reduced. Despite showing normal differentiation, both SUV39H1-deficient T H2 cells and HP1α-deficient T H2 cells, in contrast to wild-type cells, expressed T H1 genes when recultured under conditions that drive differentiation into T H1 cells. In a mouse model of T H2-driven allergic asthma, the chemical inhibition or loss of SUV39H1 skewed T-cell responses towards T H1 responses and decreased the lung pathology. These results establish a link between the SUV39H1-H3K9me3- HP1α pathway and the stability of T H2 cells, and they identify potential targets for therapeutic intervention in T H2-cell-mediated inflammatory diseases. © 2012 Macmillan Publishers Limited. All rights reserved.