T CELL RESPONSES Epigenetic Modifications at the Il2 Locus That Lead to the Silencing of This

RESEARCH HIGHLIGHTS

encoded by Ikzf3 — promotes T CELL RESPONSES epigenetic modifications at the Il2 locus that lead to the silencing of this

gene during TH17 cell differentiation. Silent commitment In keeping with this, Aiolos-deficient

T cells showed defective TH17 cell

Different T helper (TH) cell subsets suggesting that SUV39H1 and HP1α development in vitro and in vivo. drive distinct effector immune promote stable commitment to the TH2 Kinetic analyses showed that the responses, and there is much interest these studies cell lineage by ensuring that the expression of signal transducer and in their developmental pathways. Two silencing of T 1-associated genes is activator of transcription 3 (Stat3) and indicate the H recent studies, published in Nature maintained. aryl hydrocarbon receptor (Ahr) was and Nature Immunology, describe how importance of Notably, in a mouse model of upregulated prior to the expression of gene-silencing mechanisms can gene-silencing allergic asthma, SUV39H1-deficient Ikzf3, and these transcription factors promote commitment to distinct mechanisms mice showed decreased TH2 cell were found to interact with the Ikzf3 T cell lineages in mice. lineage stability and developed less promoter to drive the expression of H for stable The histone methylase SUV39H1 severe allergic inflammation in the Aiolos in TH17 cells. participates in the trimethylation of TH cell lineage lungs compared with wild-type The authors also investigated the histone H3 lysine 9 (H3K9me3), commitment controls. Mice treated with an significance of Aiolos-mediated a modification that promotes SUV39H1-specific inhibitor also had regulation of the Il2 locus during transcriptional silencing by providing lower levels of TH2-type lung disease. Using a T cell-transfer model binding sites for heterochromatin inflammation in this model, suggesting of colitis (in which increases in the protein 1α (HP1α). Allan et al. that targeting of the SUV39H1– ratio of TH1 to TH17 cells are linked addressed the role of this epigenetic H3K9me3–HP1α pathway may have with more severe wasting disease), silencing pathway in TH cell lineage therapeutic potential for treating they found that the transfer of commitment in vitro. They found that TH2 cell-associated diseases. Aiolos-deficient T cells induced more

TH1 cells had increased levels of In the other study, Quintana et al. severe pathology in lymphocyte- H3K9me3 at the promoters of described a silencing mechanism that deficient recipient mice than did the GATA-binding factor 3 (Gata3) and is important for promoting the transfer of wild-type T cells. This interleukin-4 (Il4), which are genes differentiation of TH17 cells. IL-2 enhanced pathology was associated + + associated with TH2 cell lineage inhibits TH17 cell differentiation by with higher ratios of IFNγ to IL-17 commitment. By contrast, TH2 cells interfering with IL-6-dependent T cells in the intestines of the showed increased levels of H3K9me3 signalling events, and, as such, Aiolos-deficient T cell recipients, at the promoters of Tbx21 (which commitment to the TH17 cell lineage suggesting that the failure of Aiolos to encodes T-bet) and interferon-γ (Ifng), requires downregulation of IL-2 drive TH17 cell development both of which are associated with expression. The authors found that accounted for the increased disease

TH1 cell differentiation. Aiolos — an Ikaros family member severity. To examine the importance of these Taken together, these studies H3K9 modifications, the authors indicate the importance of gene- assessed lineage commitment in T cells silencing mechanisms for stable TH cell from SUV39H1-deficient mice. lineage commitment. Furthermore, SUV39H1-deficient T cells showed they show how the aberration of such normal commitment to the TH1 or silencing pathways can affect the

TH2 cell lineages in vitro. In addition, development of pathological T cell

SUV39H1-deficient TH1 cells responses in diseased tissues. Yvonne Bordon maintained a TH1 cell phenotype when cultured under TH2-type polarizing ORIGINAL RESEARCH PAPERS Allan, R. S. et al. conditions. However, SUV39H1- An epigenetic silencing pathway controlling T helper 2 cell lineage commitment. Nature 4 Jul deficient TH2 cells that were cultured 2012 (doi:10.1038/nature11173) | Quintana, F. J. et al. Aiolos promotes T 17 differentiation by under TH1-type polarizing conditions H upregulated expression of T-bet and directly silencing Il2 expression. Nature Immunol. 1 Jul 2012 (doi:10.1038/ni.2363) IFNγ. Similar findings were observed in FURTHER READING Wilson, C. B. et al. lineage-commitment experiments Epigenetic control of T-helper-cell differentiation. Nature Rev. Immunol. 9, 91–105 (2009) using HP1α-deficient T cells, NPG

NATURE REVIEWS | IMMUNOLOGY VOLUME 12 | AUGUST 2012