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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 maintenance of TH2 lineage commitment. In the TH2 cell subset, the master regulator of TH1 cells (Tbx21) is silenced. The histone methylase Suv39H1 adds the repressive H3K9me3 mark at the Tbx21 locus. This initiates recruitment and docking of heterochromatin protein 1 alpha (HP1α), histone deacetylase (HDAC) 1 and 2, and methyl-binding domain protein (MBD1). HDACs then remove the active H3K9ac mark to maintain silencing, mediated by H3K9me3, at the Tbx21 locus.
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Figure 5: Epigenetic maintenance of TH2 lineage commitment. In the TH2 cell subset, the master regulator of TH1 cells (Tbx21) is silenced. The histone methylase Suv39H1 adds the repressive H3K9me3 mark at the Tbx21 locus. This initiates recruitment and docking of heterochromatin protein 1 alpha (HP1α), histone deacetylase (HDAC) 1 and 2, and methyl-binding domain protein (MBD1). HDACs then remove the active H3K9ac mark to maintain silencing, mediated by H3K9me3, at the Tbx21 locus.

Mentions: Taken together, these data demonstrate that Suv39H1 acts to specifically promote TH2 lineage commitment via epigenetic silencing (via H3K9me3 deposition) of gene loci that drive TH1 fate commitment (Figure 5). One interesting observation was the fact that despite TH2 cells exhibiting an overall repressive signature within the Tbx21 locus, there is still evidence of H3K4me3 deposition at the promoter. Thus, pharmacological interventions that block Suv39H1 activity could serve to promote Tbx21 transcription and subsequent TH1 gene expression. The clinical relevance was made apparent when treatment of mice with a Suv39H1 inhibitor, was able to ameliorate TH2 cell driven tissue damage in a model of allergic asthma. Treatment of mice resulted in higher numbers of TH1 T cells, and redirected the immune response toward a less pathogenic state. This study highlights the potential for manipulating epigenetic programing of effector T cell responses using small molecule inhibitors to either promote immunity, in the case of vaccination, or suppress the damage caused by inappropriate immune responses, as is found in autoimmune disease or allergy.


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 maintenance of TH2 lineage commitment. In the TH2 cell subset, the master regulator of TH1 cells (Tbx21) is silenced. The histone methylase Suv39H1 adds the repressive H3K9me3 mark at the Tbx21 locus. This initiates recruitment and docking of heterochromatin protein 1 alpha (HP1α), histone deacetylase (HDAC) 1 and 2, and methyl-binding domain protein (MBD1). HDACs then remove the active H3K9ac mark to maintain silencing, mediated by H3K9me3, at the Tbx21 locus.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: Epigenetic maintenance of TH2 lineage commitment. In the TH2 cell subset, the master regulator of TH1 cells (Tbx21) is silenced. The histone methylase Suv39H1 adds the repressive H3K9me3 mark at the Tbx21 locus. This initiates recruitment and docking of heterochromatin protein 1 alpha (HP1α), histone deacetylase (HDAC) 1 and 2, and methyl-binding domain protein (MBD1). HDACs then remove the active H3K9ac mark to maintain silencing, mediated by H3K9me3, at the Tbx21 locus.
Mentions: Taken together, these data demonstrate that Suv39H1 acts to specifically promote TH2 lineage commitment via epigenetic silencing (via H3K9me3 deposition) of gene loci that drive TH1 fate commitment (Figure 5). One interesting observation was the fact that despite TH2 cells exhibiting an overall repressive signature within the Tbx21 locus, there is still evidence of H3K4me3 deposition at the promoter. Thus, pharmacological interventions that block Suv39H1 activity could serve to promote Tbx21 transcription and subsequent TH1 gene expression. The clinical relevance was made apparent when treatment of mice with a Suv39H1 inhibitor, was able to ameliorate TH2 cell driven tissue damage in a model of allergic asthma. Treatment of mice resulted in higher numbers of TH1 T cells, and redirected the immune response toward a less pathogenic state. This study highlights the potential for manipulating epigenetic programing of effector T cell responses using small molecule inhibitors to either promote immunity, in the case of vaccination, or suppress the damage caused by inappropriate immune responses, as is found in autoimmune disease or allergy.

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