Naïve CD4+ T helper (Th) cells acquire a range of fates depending on the cytokine milieu and anatomical location. For example, IL-17 producing Th17 and Foxp3+ regulatory (Treg) cells are dependent upon TGFβ1 and are critical for intestinal homeostasis. G9a is a histone lysine methyltransferase with di-methyl activity towards histone H3 lysine 9. H3K9me2 is a highly conserved histone modification and is commonly linked to transcriptional repression. In this study we examine the role of G9a in the control of Th17 and Treg cell differentiation. Using chromatin immunoprecipitation (ChIP) we found that there is a concomitant loss H3K9me2 and increase in H3K9Ac (an activating histone modification) at lineage specific genes of WT Th17 and Treg cells compared to naive. Meanwhile, naïve G9a-/- T cells have low levels H3K9me2 that results in enhanced sensitivity to TGFβ1 and an increase in the differentiation of both Th17 and Treg cells in vitro. Using the T cell transfer colitis model, we found that transfer of G9a-deficient T cells fails to cause the weight loss and colonic inflammation typical of the model. Furthermore, T effector-cell production of IFNγ was significantly reduced and IL-17 was enhanced when G9a-/- T cells were transferred. In addition, compared to WT controls, a higher proportion of G9a-deficient T cells express Foxp3. We conclude that G9a-dependent H3K9me2 is a homeostatic epigenetic checkpoint that controls the magnitude of Th17 and Treg cell responses.
- Copyright © 2013 by The American Association of Immunologists, Inc.