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T cell immunity as a tool for studying epigenetic regulation of cellular differentiation.

Russ BE, Prier JE, Rao S, Turner SJ - Front Genet (2013)

Bottom Line: This is achieved, in part, by regulating changes in histone post-translational modifications (PTMs) and DNA methylation that in turn, impact transcriptional activity.Cardinal features of adaptive T cell immunity include the ability to differentiate in response to infection, resulting in acquisition of immune functions required for pathogen clearance; and the ability to maintain this functional capacity in the long-term, allowing more rapid and effective pathogen elimination following re-infection.These characteristics underpin vaccination strategies by effectively establishing a long-lived T cell population that contributes to an immunologically protective state (termed immunological memory).

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, The University of Melbourne Parkville, VIC, Australia.

ABSTRACT
Cellular differentiation is regulated by the strict spatial and temporal control of gene expression. This is achieved, in part, by regulating changes in histone post-translational modifications (PTMs) and DNA methylation that in turn, impact transcriptional activity. Further, histone PTMs and DNA methylation are often propagated faithfully at cell division (termed epigenetic propagation), and thus contribute to maintaining cellular identity in the absence of signals driving differentiation. Cardinal features of adaptive T cell immunity include the ability to differentiate in response to infection, resulting in acquisition of immune functions required for pathogen clearance; and the ability to maintain this functional capacity in the long-term, allowing more rapid and effective pathogen elimination following re-infection. These characteristics underpin vaccination strategies by effectively establishing a long-lived T cell population that contributes to an immunologically protective state (termed immunological memory). As we discuss in this review, epigenetic mechanisms provide attractive and powerful explanations for key aspects of T cell-mediated immunity - most obviously and notably, immunological memory, because of the capacity of epigenetic circuits to perpetuate cellular identities in the absence of the initial signals that drive differentiation. Indeed, T cell responses to infection are an ideal model system for studying how epigenetic factors shape cellular differentiation and development generally. This review will examine how epigenetic mechanisms regulate T cell function and differentiation, and how these model systems are providing general insights into the epigenetic regulation of gene transcription during cellular differentiation.

No MeSH data available.


Related in: MedlinePlus

Epigenetic reprogramming within effector gene loci of CD8+ memory T cells enables rapid effector function.(A) In naïve CD8+ T cells, effector loci such as Ifng display repressive epigenetic marks e.g., H3K27me3 and is inaccessible to transcriptional machinery due to the heterochromatin structure. Upon activation, the chromatin is remodelled whereby it acquires active epigenetic marks e.g., H3K4me3 at key effector loci and nucleosome exit to make the loci accessible by transcriptional machinery and RNA polymerase II (RNAp), allowing transcription. Upon differentiation to memory CD8+ T cells, the chromatin retains the permissive H3K4me3 mark and RNAp remains docked. (B) Upon re-infection, the effector loci in memory CD8+ T cells is poised and can undergo rapid transcription.
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Figure 4: Epigenetic reprogramming within effector gene loci of CD8+ memory T cells enables rapid effector function.(A) In naïve CD8+ T cells, effector loci such as Ifng display repressive epigenetic marks e.g., H3K27me3 and is inaccessible to transcriptional machinery due to the heterochromatin structure. Upon activation, the chromatin is remodelled whereby it acquires active epigenetic marks e.g., H3K4me3 at key effector loci and nucleosome exit to make the loci accessible by transcriptional machinery and RNA polymerase II (RNAp), allowing transcription. Upon differentiation to memory CD8+ T cells, the chromatin retains the permissive H3K4me3 mark and RNAp remains docked. (B) Upon re-infection, the effector loci in memory CD8+ T cells is poised and can undergo rapid transcription.

Mentions: For example, upon differentiation from a naïve TH state into the various TH subsets, H3K4me3 deposition was observed at signature effector gene loci within distinct TH subsets (e.g., Ifng in TH1, Il4 in TH2, and Il17 in TH17). Moreover, H3K27me3 deposition was correlated with transcriptional shutdown of effector gene loci that are characteristic of other TH subsets (Wei et al., 2009; Table 1). One might have expected that changes in the epigenetic signatures within gene loci encoding lineage-defining TFs, would simply reflect those observed for lineage-specific effector gene loci. For example, the gene locus encoding the TH17 TF Rorc (retinoid-related orphan receptor-γ) was decorated with H3K27me3 in the naïve state, and only acquired H3K4me3, and losing H3K27me3 after TH17 differentiation. In contrast, the repressive H3K27me3 signature was reinforced under TH1 and TH2 differentiation conditions (Araki et al., 2009). However, this was not always the case. The Tbx21 (TH1) and Gata3 (TH2) gene loci in naïve TH cells were marked with both H3K4me3 and H3K27me3 (termed bivalent loci), and whilst these loci resolved to a permissive epigenetic signature (H3K4me3+/H3K27me3-) under TH1 and TH2 differentiation conditions, respectively, they did not acquire a repressive epigenetic signature when differentiated into opposing lineages, but rather maintained a bivalent state (Figure 4). Similarly, the Tbx21 locus within TH17 cells was also maintained in a bivalent state. In the case of TH17 cells, re-stimulation of TH17 cells in the presence of IL-12 resulted in expression of IFN-γ and conversion to a TH1 phenotype. This was associated with acquisition of permissive epigenetic signatures at the IFN-γ locus and IL-12-dependent STAT-4 and Tbx21-dependent epigenetic silencing of the TH17 associated Rorc locus (Mukasa et al., 2010). Given that epigenetic bivalency is considered a mechanism for poising gene loci for rapid activation or repression, these data suggest that CD4+ TH subsets can maintain some level of functional plasticity despite lineage commitment. It is tempting to speculate that this provides the immune system with inherent flexibility, allowing the redirection of pathogen-specific TH responses. In the case of TH17 cells, it may represent a mechanism that enables switching from a potent inflammatory TH17 response to a less damaging, more controlled effector response. It also suggests that targeted interventions that drive epigenetic reprograming of TH responses involved in autoimmune diseases (such as TH17 in the context of multiple sclerosis) might represent novel immunotherapeutic targets that could lead to decreased pathology.


T cell immunity as a tool for studying epigenetic regulation of cellular differentiation.

Russ BE, Prier JE, Rao S, Turner SJ - Front Genet (2013)

Epigenetic reprogramming within effector gene loci of CD8+ memory T cells enables rapid effector function.(A) In naïve CD8+ T cells, effector loci such as Ifng display repressive epigenetic marks e.g., H3K27me3 and is inaccessible to transcriptional machinery due to the heterochromatin structure. Upon activation, the chromatin is remodelled whereby it acquires active epigenetic marks e.g., H3K4me3 at key effector loci and nucleosome exit to make the loci accessible by transcriptional machinery and RNA polymerase II (RNAp), allowing transcription. Upon differentiation to memory CD8+ T cells, the chromatin retains the permissive H3K4me3 mark and RNAp remains docked. (B) Upon re-infection, the effector loci in memory CD8+ T cells is poised and can undergo rapid transcription.
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Figure 4: Epigenetic reprogramming within effector gene loci of CD8+ memory T cells enables rapid effector function.(A) In naïve CD8+ T cells, effector loci such as Ifng display repressive epigenetic marks e.g., H3K27me3 and is inaccessible to transcriptional machinery due to the heterochromatin structure. Upon activation, the chromatin is remodelled whereby it acquires active epigenetic marks e.g., H3K4me3 at key effector loci and nucleosome exit to make the loci accessible by transcriptional machinery and RNA polymerase II (RNAp), allowing transcription. Upon differentiation to memory CD8+ T cells, the chromatin retains the permissive H3K4me3 mark and RNAp remains docked. (B) Upon re-infection, the effector loci in memory CD8+ T cells is poised and can undergo rapid transcription.
Mentions: For example, upon differentiation from a naïve TH state into the various TH subsets, H3K4me3 deposition was observed at signature effector gene loci within distinct TH subsets (e.g., Ifng in TH1, Il4 in TH2, and Il17 in TH17). Moreover, H3K27me3 deposition was correlated with transcriptional shutdown of effector gene loci that are characteristic of other TH subsets (Wei et al., 2009; Table 1). One might have expected that changes in the epigenetic signatures within gene loci encoding lineage-defining TFs, would simply reflect those observed for lineage-specific effector gene loci. For example, the gene locus encoding the TH17 TF Rorc (retinoid-related orphan receptor-γ) was decorated with H3K27me3 in the naïve state, and only acquired H3K4me3, and losing H3K27me3 after TH17 differentiation. In contrast, the repressive H3K27me3 signature was reinforced under TH1 and TH2 differentiation conditions (Araki et al., 2009). However, this was not always the case. The Tbx21 (TH1) and Gata3 (TH2) gene loci in naïve TH cells were marked with both H3K4me3 and H3K27me3 (termed bivalent loci), and whilst these loci resolved to a permissive epigenetic signature (H3K4me3+/H3K27me3-) under TH1 and TH2 differentiation conditions, respectively, they did not acquire a repressive epigenetic signature when differentiated into opposing lineages, but rather maintained a bivalent state (Figure 4). Similarly, the Tbx21 locus within TH17 cells was also maintained in a bivalent state. In the case of TH17 cells, re-stimulation of TH17 cells in the presence of IL-12 resulted in expression of IFN-γ and conversion to a TH1 phenotype. This was associated with acquisition of permissive epigenetic signatures at the IFN-γ locus and IL-12-dependent STAT-4 and Tbx21-dependent epigenetic silencing of the TH17 associated Rorc locus (Mukasa et al., 2010). Given that epigenetic bivalency is considered a mechanism for poising gene loci for rapid activation or repression, these data suggest that CD4+ TH subsets can maintain some level of functional plasticity despite lineage commitment. It is tempting to speculate that this provides the immune system with inherent flexibility, allowing the redirection of pathogen-specific TH responses. In the case of TH17 cells, it may represent a mechanism that enables switching from a potent inflammatory TH17 response to a less damaging, more controlled effector response. It also suggests that targeted interventions that drive epigenetic reprograming of TH responses involved in autoimmune diseases (such as TH17 in the context of multiple sclerosis) might represent novel immunotherapeutic targets that could lead to decreased pathology.

Bottom Line: This is achieved, in part, by regulating changes in histone post-translational modifications (PTMs) and DNA methylation that in turn, impact transcriptional activity.Cardinal features of adaptive T cell immunity include the ability to differentiate in response to infection, resulting in acquisition of immune functions required for pathogen clearance; and the ability to maintain this functional capacity in the long-term, allowing more rapid and effective pathogen elimination following re-infection.These characteristics underpin vaccination strategies by effectively establishing a long-lived T cell population that contributes to an immunologically protective state (termed immunological memory).

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, The University of Melbourne Parkville, VIC, Australia.

ABSTRACT
Cellular differentiation is regulated by the strict spatial and temporal control of gene expression. This is achieved, in part, by regulating changes in histone post-translational modifications (PTMs) and DNA methylation that in turn, impact transcriptional activity. Further, histone PTMs and DNA methylation are often propagated faithfully at cell division (termed epigenetic propagation), and thus contribute to maintaining cellular identity in the absence of signals driving differentiation. Cardinal features of adaptive T cell immunity include the ability to differentiate in response to infection, resulting in acquisition of immune functions required for pathogen clearance; and the ability to maintain this functional capacity in the long-term, allowing more rapid and effective pathogen elimination following re-infection. These characteristics underpin vaccination strategies by effectively establishing a long-lived T cell population that contributes to an immunologically protective state (termed immunological memory). As we discuss in this review, epigenetic mechanisms provide attractive and powerful explanations for key aspects of T cell-mediated immunity - most obviously and notably, immunological memory, because of the capacity of epigenetic circuits to perpetuate cellular identities in the absence of the initial signals that drive differentiation. Indeed, T cell responses to infection are an ideal model system for studying how epigenetic factors shape cellular differentiation and development generally. This review will examine how epigenetic mechanisms regulate T cell function and differentiation, and how these model systems are providing general insights into the epigenetic regulation of gene transcription during cellular differentiation.

No MeSH data available.


Related in: MedlinePlus