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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

Bivalency of master regulator gene loci in TH1 and TH2 cells. Prior to differentiation of TH0 cells into the TH1 or TH2 cell subsets, the master regulator loci of each subset, Tbx21 and Gata3 respectively, have both active H3K4me3 and repressive H3K27me3 marks. The bivalent Tbx21 locus loses the repressive H3K27me3 mark upon differentiation into TH1 cells. However, the Gata3 locus remains bivalent. The reverse is true for TH2 cells whereby Gata3 loses the repressive H3K27me3 mark yet retains bivalency at the Tbx21 locus.
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Figure 3: Bivalency of master regulator gene loci in TH1 and TH2 cells. Prior to differentiation of TH0 cells into the TH1 or TH2 cell subsets, the master regulator loci of each subset, Tbx21 and Gata3 respectively, have both active H3K4me3 and repressive H3K27me3 marks. The bivalent Tbx21 locus loses the repressive H3K27me3 mark upon differentiation into TH1 cells. However, the Gata3 locus remains bivalent. The reverse is true for TH2 cells whereby Gata3 loses the repressive H3K27me3 mark yet retains bivalency at the Tbx21 locus.

Mentions: As mentioned earlier, memory T cells maintain the capacity for rapid effector gene expression without the need for further differentiation. Strikingly, the permissive signature within the Ifng promoter of effector CD8+ killer T cells is maintained into long-term memory. Further, although memory CD8+ killer T cells exhibit little Ifng transcriptional activity prior to re-infection, RNA polymerase (RNAp) is docked at the Ifng promoter (Denton et al., 2011; Zediak et al., 2011). Taken together, these data suggest that the ability of memory cells to produce IFN-γ rapidly following re-infection is due to the promoter being maintained in a transcriptionally permissive state, and that the rate-limiting step in re-expression of IFN-γ is transcriptional initiation (Figures 3A,B). It remains to be determined whether transcriptional poising (as measured by RNAp docking) at other effector gene loci with low transcriptionally activity is evident within memory CD8+ killer T cells. Further, it would be of particular interest to determine the extent of transcriptional poising in memory T cells at a genome-wide level and compare this to naïve and effector cells. In this way, it could determined to what extent transcriptional poising underpins memory T cell characteristics. Moreover, given the direct effect of acetylation on nucleosome density, increased acetylation in memory cells (Araki et al., 2008; Denton et al., 2011) may explain their ability to produce more IFN-γ upon re-infection (La Gruta et al., 2004). In this way, memory T cells are reconfigured at the chromatin level to exhibit more potent effector function and this, in turn, helps ensure more effective and more rapid control of a secondary infection.


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

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

Bivalency of master regulator gene loci in TH1 and TH2 cells. Prior to differentiation of TH0 cells into the TH1 or TH2 cell subsets, the master regulator loci of each subset, Tbx21 and Gata3 respectively, have both active H3K4me3 and repressive H3K27me3 marks. The bivalent Tbx21 locus loses the repressive H3K27me3 mark upon differentiation into TH1 cells. However, the Gata3 locus remains bivalent. The reverse is true for TH2 cells whereby Gata3 loses the repressive H3K27me3 mark yet retains bivalency at the Tbx21 locus.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3824109&req=5

Figure 3: Bivalency of master regulator gene loci in TH1 and TH2 cells. Prior to differentiation of TH0 cells into the TH1 or TH2 cell subsets, the master regulator loci of each subset, Tbx21 and Gata3 respectively, have both active H3K4me3 and repressive H3K27me3 marks. The bivalent Tbx21 locus loses the repressive H3K27me3 mark upon differentiation into TH1 cells. However, the Gata3 locus remains bivalent. The reverse is true for TH2 cells whereby Gata3 loses the repressive H3K27me3 mark yet retains bivalency at the Tbx21 locus.
Mentions: As mentioned earlier, memory T cells maintain the capacity for rapid effector gene expression without the need for further differentiation. Strikingly, the permissive signature within the Ifng promoter of effector CD8+ killer T cells is maintained into long-term memory. Further, although memory CD8+ killer T cells exhibit little Ifng transcriptional activity prior to re-infection, RNA polymerase (RNAp) is docked at the Ifng promoter (Denton et al., 2011; Zediak et al., 2011). Taken together, these data suggest that the ability of memory cells to produce IFN-γ rapidly following re-infection is due to the promoter being maintained in a transcriptionally permissive state, and that the rate-limiting step in re-expression of IFN-γ is transcriptional initiation (Figures 3A,B). It remains to be determined whether transcriptional poising (as measured by RNAp docking) at other effector gene loci with low transcriptionally activity is evident within memory CD8+ killer T cells. Further, it would be of particular interest to determine the extent of transcriptional poising in memory T cells at a genome-wide level and compare this to naïve and effector cells. In this way, it could determined to what extent transcriptional poising underpins memory T cell characteristics. Moreover, given the direct effect of acetylation on nucleosome density, increased acetylation in memory cells (Araki et al., 2008; Denton et al., 2011) may explain their ability to produce more IFN-γ upon re-infection (La Gruta et al., 2004). In this way, memory T cells are reconfigured at the chromatin level to exhibit more potent effector function and this, in turn, helps ensure more effective and more rapid control of a secondary infection.

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