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Review
. 2018 Dec 12:9:2929.
doi: 10.3389/fimmu.2018.02929. eCollection 2018.

Epigenetic and Transcriptional Regulation in the Induction, Maintenance, Heterogeneity, and Recall-Response of Effector and Memory Th2 Cells

Atsushi Onodera  1   2 , Kota Kokubo  1 , Toshinori Nakayama  1
Affiliations
Review

Epigenetic and Transcriptional Regulation in the Induction, Maintenance, Heterogeneity, and Recall-Response of Effector and Memory Th2 Cells

Atsushi Onodera et al. Front Immunol. .

Abstract

Antigen-primed T cells respond to restimulation much faster than naïve T cells and form the cellular basis of immunological memory. The formation of memory Th2 cells starts when naïve CD4 T cells are transformed into effector Th2 cells and is completed after antigen clearance and a long-term resting phase accompanied by epigenetic changes in the Th2 signature genes. Memory Th2 cells maintain their functions and acquired heterogeneity through epigenetic machinery, on which the recall-response of memory Th2 cells is also dependent. We provide an overview of the epigenetics in the whole Th2 cell cycle, mainly focusing on two different histone lysine methyltransferase complexes: the Polycomb and Trithorax groups. We finally discuss the pathophysiology and potential therapeutic strategies for the treatment of Th2-mediated inflammatory diseases in mice and humans.

Keywords: GATA3; airway infiammation; allergic disease; pathogenic Th2 (Tpath2) cells; polycomb and trithorax.

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Figures

Figure 1
Figure 1
Polycomb (PcG) and Trithorax (TrxG) complexes in mammals. Two basic types of Polycomb repressive complex 1 (PRC1) and PRC2 are shown (upper). Canonical PRC1 consists of four core subunits: RING1A/B, PCGF, CBX, and PHC (1, 15, 16). PCGF and RING1A/B, which ubiquitinate H2AK119, also compose non-canonical PRC1 (15). PCGF4 is also known as Bmi1. PRC2 consists of four core subunits: EZH1/2, EED, SUZ12, and RBBP4/7. The SET domain of EZH1/2 is responsible for PRC2 methylase activity. In contrast, mammalian cells have six H3K4 methylases: MLL1-4, SET1A, and SET1B (lower) (, –17). All of these complexes share ASH2L, RBBP5, DPY30, WDR5, and HCF1, which is a substoichiometric component that is absent in some branches of the TrxG complexes (green) (17). Menin is a unique subunit of MLL1/2 complexes (blue). MLL3/4 complexes are uniquely associated with PTIP, PA1, UTX, and NCOA6, while SET1A/B complexes are specifically associated with WDR82 and CXXC1 (shown in blue). This figure was reproduced with permission provided by Annual Reviews copyright transfer agreement [originally published by Nakayama et al. (1)].
Figure 2
Figure 2
(A) The epigenetic regulation of the induction, maintenance, and recall-response of effector and memory Th2 cells (1, 22). In naïve CD4 T cells, which express a moderate level of Gata3 mRNA, the PcG proteins bind to the region between the distal and proximal promoter of the Gata3 gene. After receiving signals via the T cell receptors (TCRs) in the presence of IL-4, activated STAT6 proteins bind to the Gata3 gene locus, resulting in disassociation of the PcG complex and spreading of the TrxG complex binding to the region between the distal and proximal promoters. Extremely high Gata3 mRNA expression levels are achieved “in an IL-4/STAT6-dependent but TrxG-independent manner” in developing Th2 cells (1, 22). During Th2 cell differentiation TrxG is also recruited to the Il4 gene locus and induces H3K4 methylation and H3K9 acetylation in collaboration with GATA3 proteins. Once Th2 cells are differentiated, the TrxG protein binding is observed from the proximal promoter to intron 3 of the Gata3 gene accompanied by a broad range of H3K9ac and H3K4me3. This TrxG binding pattern may be preserved during the process of generating memory Th2 cells from effector Th2 cells. The TrxG complex bound to the Gata3 locus can maintain the strong expression of Gata3 in memory Th2 cells where the transcription of Gata3 is regulated “in an IL-4/STAT6-independent but TrxG-dependent manner” (1, 22). Note that in memory Th2 cells, the protein expression of GATA3 is slightly decreased in comparison to effector Th2 cells because GATA3 proteins are unstable in resting conditions. When memory Th2 cells reencounter their cognate antigens and a recall-response is induced, the GATA3 protein expression is immediately upregulated to produce large amounts of Th2 cytokines. TrxG proteins bound to the Il4 gene also play an important role in the expression of IL-4 in memory Th2 cells. This figure was reproduced according to the permissions policy of Rockefeller University Press Journals © 2010 Onodera et al. (B) The spatial interplay between Polycomb (PcG) and Trithorax (TrxG) proteins. In CD4 T cells, the binding position of PcG and TrxG proteins relative to the transcription start site (TSS) of a gene is connected to its expression (1, 23). PcG and TrxG proteins show an exclusive binding pattern at the TSS of some genes: PcG is observed to bind downstream of the TSS while TrxG binds upstream of the TSS in genes with lower transcription levels (Gene A); in contrast, PcG is observed to bind upstream of the TSS while TrxG binds downstream of the TSS in genes with higher transcription levels (Gene C). When TrxG proteins bind throughout a gene, the gene shows an extremely high transcription level (Gene D). When PcG and TrxG proteins are bound in a similar position relative to the TSS, the transcription level of this gene is expected to be moderate (Gene B). This figure was reproduced according to the permissions policy of ASM Journals Copyright © Onodera et al. (23).
Figure 3
Figure 3
The two types of pathogenic memory Th2 (Tpath2) cells. Antigens that are potentially associated with allergic reactions promote the secretion of IL-33 from airway epithelial cells. IL-33 binds to its receptor ST2 on memory Th2 cells and induces epigenetic changes of the Il5 gene, resulting in the generation of IL-5-producing Tpath2 cells (upper) (1, 87). When Tpath2 cells reencounter their cognate antigens, these cells produce a large amount of IL-5, which exacerbates chronic eosinophilic inflammation in the lung. IL-33 also induces the production of fibrosis-inducing Tpath2 cells, which produce large amounts of Amphiregulin (lower) (88). Amphiregulin binds to the epidermal growth factor receptors (EGFRs) on eosinophils and induces Osteopontin secretion from the eosinophils, resulting in fibrosis in the lung tissue. This figure was reproduced according to the permissions policy of Cell Press journal [originally published by Morimoto et al. (88)].
Figure 4
Figure 4
The “CD69-Myl9 system.” In the inflamed lung, platelet-derived Myl9 forms a net-like structure in association with platelets on the luminal surface of blood vessels (92, 93). CD69 molecules on effector Th2 cells interact with Myl9 nets and help Th2 cells infiltrate tissues. Infiltrating Th2 cells reencounter their cognate antigens and exert effector functions through the production of Th2 cytokines. IL-5 is known to recruit eosinophils whereas IL-13 promotes mucus hyperproduction from airway epithelial cells. IL-4 stimulates Th2 proliferation in an autocrine manner. This figure was reproduced according to the permissions policy of John Wiley & Sons publications [originally published by Kimura et al. (93)].
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