Epigenetics – the Key to Understand Immune Responses in Health and Disease
Ola Winqvist, Department of Medicine, Unit of Clinical Allergy Research L2:04, Karolinska University Hospital, S-171 76 Stockholm, Sweden.
Citation Janson PC, Winqvist O. Epigenetics – the Key to Understand Immune Responses in Health and Disease. Am J Reprod Immunol 2011; 66 (Suppl. 1): 72–74
Problem Development of alternative CD4+ T cells provides flexibility to the immune system. This is crucial for the initiation of appropriate effector mechanisms to protect against various pathogens such as bacteria, viruses, tumors, and parasites.
Method of study Review of research on the epigenetic regulation of T-cell subsets.
Results Studies of the epigenetic modulation of T-cell subset function/dysfunction during the past years have increased our understanding of how the alternative effector populations arise and how their identity is maintained during clonal expansion.
Conclusions The recent advances in epigenetic research within the field of immunology have also raised questions on how immunology is regulated during pregnancy and early life and how epigenetic regulation of the immune system during prenatal development is related to diseases later in life such as autoimmunity and allergy.
The intriguing complexity of the immune system has been unraveled during recent years. The known set of cell types and subtypes increases steadily and brings the questions of what factors control cell differentiation and by what means? Epigenetic control of genes, i.e. modifications to chromatin that regulate gene expression without affecting the primary DNA sequence, is an intense field of research that has great implications for basic and clinical immunology. Recent advances have highlighted the importance of epigenetic regulation of gene expression patterns during development of the pluripotent naïve T-helper cell into its effector subpopulations.
The eukaryotic nucleus harbors genetic information consisting of several billion nucleotides. To fit all this genetic information into a nucleus, a few microns in size, DNA is tightly packed onto nucleosomes. This tightly packed structure is however virtually inaccessible for the transcriptional machinery, and a prerequisite for the transcription of a certain gene segment is the structural alteration of the gene loci in question. Nucleosome repositioning, posttranslational modification of histone tails, and methylation of CpG dinucleotides constitute different levels of chromatin modifications, which ultimately affect DNA accessibility. These structural alterations occur in a highly ordered fashion, where selective modifications allow for tissue-specific expression and heritability, two hallmarks of epigenetic regulation.1
Posttranslational modifications to histones
Posttranslational histone modifications include acetylation, methylation, ubiquitylation, phosphorylation, and SUMOylation. To further increase the complexity, many of the modifications occur multiple times at the same residue of a histone tail. Acetylation is the most frequently studied histone modification and is usually localized to active chromatin. Methylation, on the other hand, plays a dual role as it is important in both transcription and repression, depending on where the methyl group is situated. Trimethylation of lysine four in histone H3 (H3K4me3), for instance, is associated with transcriptional activity. By contrast, trimethylation of lysine nine (H3K9me3) or lysine 27 (H3K27me3) is a modification found in heterochromatin.1 Acetylation brings negative charge to histones, thereby increasing the repelling forces between the nucleosomes and the DNA, which opens up the chromatin structure. Secondly, other modifications, such as methylation, permit binding of protein complexes with chromatin-modulating properties without affecting the charge.
DNA methylation occurs predominantly on CpG dinucleotides and is associated with transcriptional repression. CpG dinucleotides are often found accumulated in conserved regulatory regions (CpG islands) demonstrating their functional importance.2 DNA methylation as a preserver of cellular identity is more rigid than histone modifications. Methylation pattern is maintained with high fidelity through cell divisions by the recruitment of maintenance methylase 1 (Dnmt1) to the DNA replication fork, where methyl groups are added to the newly synthesized daughter strand, using the mother strand as a template.
Methylation of CpGs can repress transcription either directly by inhibiting the binding of transcription factors and/or co-activators to regulatory elements or by secondary effects through the recruitment of histone modifying complexes to methyl-binding proteins.3 Chromatin-modulating complexes can also recruit DNA methyltransferases; thus, there exists a bidirectional interplay between DNA methylation and histone modifications.4
Epigenetic regulation of T-helper cell development
The naïve T-helper cell has some level of pluripotent capacity, i.e. it can develop into one of several distinct T-helper effector lineages, each with a separate cytokine secretion profile that promotes different effector functions. T-helper type 1 (Th1) cells produce IFN-γ and provide protection against intracellular pathogens and cancer. T-helper type 2 (Th2) cells are characterized by the cytokines IL-4, IL-5, and IL-13, which stimulate B-cell antibody production and are involved in host defense against parasites.5 The recently discovered Th17 cells are involved in neutrophil-mediated protection against extracellular bacteria and produce the cytokines IL-17A, IL-17F, IL-21, and IL-22. Finally, the regulatory T cells (Tregs), characterized by a continuous expression of the transcription factor FOXP3, have a crucial role in maintaining homeostasis of the immune system and in preventing the autoimmune reactivity of self-reactive T cells.6
Cell lineage decision in T-helper cells is influenced by the surrounding cytokine milieu at the site of antigen encounter. The intracellular signaling pathways downstream of cytokine receptors induce the expression of cell lineage–specific transcription factors, with the ability to induce chromatin remodeling within their DNA-binding regions.
During Th1 and Th2 polarization, DNA demethylation and permissive histone marks increase the accessibility of conserved regulatory elements surrounding the IFNG locus and the Th2 locus (containing the IL-4, IL-5, and IL-13 genes), thereby reinforcing the transcriptional activity of IFN-γ and Th2 cytokines. To prevent inappropriate cytokine expression during lineage commitment, repressive histone marks and DNA hypermethylation are established at the IFNG locus (Th2 polarization) as well as in the genomic region encoding IL-4, IL-5, and IL-13 (Th1 polarization).7
In naturally occurring CD4+CD25hi Tregs (nTregs), demethylation of regulatory elements of the FOXP3 locus is a prerequisite for stable expression of FOXP3 and maintenance of a suppressive phenotype.8–10 Permissive histone modifications accumulate at the IL-17A and IL-17F loci during Th17 differentiation, suggesting epigenetic modifications as a mechanism for regulating IL-17 production also.11
The increasing evidence for epigenetic involvement in the immune system raises questions of how epigenetic changes contribute to immune dysregulation and immune diseases. Autoimmunity and allergy are two situations where the pathogenesis can (at least in part) be attributed to an imbalance of the T-helper cell responses. Th1 and Th17 cells have for example been implicated in autoimmunity, whereas allergic conditions are connected to the effector cytokines of the Th2 lineage. This section describes some clinical situations where epigenetic regulation of T-helper cells is known to play a role in disease development. The prenatal environment is biased away from a potentially harmful cytotoxic Th1 milieu. The Th1 effector arm does not mature until early childhood, which suggests failure of Th2 silencing during maturation of the immune system as a mechanism of Th2-mediated disease development.12 To our knowledge, there is still no direct evidence of epigenetic dysregulation in CD4+ cells from atopics or allergic patients; however, alterations in CpG methylation patterns have been observed in CD8+ cells from atopic individuals. Elevated IFN-γ levels have been reported in atopic individuals, especially among children, where hyperproduction of IFN-γ from CD8+ cells has been linked to a more severe symptomatology. Consistent with this, CD8+ T cells from atopic children display a hypomethylated IFNG promoter compared with healthy controls.13
Studies of epigenetic regulation of key T-cell effector genes will teach us more about the diseases where an imbalance between Th1 and Th2 cells has been suggested and hoped to provide means of restoring balance to reinforce immunohomeostasis.
This work was supported by the Swedish cancer society, the Wallenberg foundation and IMTAC.