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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

CD4+ TH – cell subset differentiation. CD4+ T cells show remarkable plasticity and are able to differentiate into many different subsets based on the soluble molecules secreted during priming of the subsets by antigen presenting cells (APC), e.g., IL-12 for TH1 cells. The different subsets can be distinguished by the transcription factors that regulate and maintain their lineage-specific effector functions, e.g., T-bet for TH1 cells. The molecules secreted by these subsets, e.g., IFN-γ for TH1 cells, are finely tuned to control the pathogen that mediated the release of the specific molecules by the APC during activation of the TH0 cells into the various subsets.
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Figure 2: CD4+ TH – cell subset differentiation. CD4+ T cells show remarkable plasticity and are able to differentiate into many different subsets based on the soluble molecules secreted during priming of the subsets by antigen presenting cells (APC), e.g., IL-12 for TH1 cells. The different subsets can be distinguished by the transcription factors that regulate and maintain their lineage-specific effector functions, e.g., T-bet for TH1 cells. The molecules secreted by these subsets, e.g., IFN-γ for TH1 cells, are finely tuned to control the pathogen that mediated the release of the specific molecules by the APC during activation of the TH0 cells into the various subsets.

Mentions: An important feature of T cell immunity is the enormous proliferative potential and functional plasticity of naïve T cells. Acquisition of lineage-specific T cell effector functions is clearly linked to an extended proliferative response, suggesting that T cell activation engages a differentiation program that facilitates effector gene expression (Gett and Hodgkin, 1998; Lawrence and Braciale, 2004; Jenkins et al., 2008). An example of T cell functional plasticity is found after activation of naïve TH cells that have the potential to differentiate into distinct T cell subsets, largely defined by the soluble effector molecules they secrete (Figure 2; Zhu et al., 2010). The best characterized of these are the TH1 and TH2 subsets, however, other subsets include TH17, Tregs (regulatory T cells), TFH (follicular TH cells) and the more recently described TH9 cells (Figure 2). TH1 and TH2 T cells are best characterized by their capacity to secrete interferon-gamma (IFN-γ) and interleukin (IL)-4, respectively. The tailoring of TH cell responses into distinct functional lineages is a consequence of integration of multiple signals that are present during initial T cell activation (Figure 2). For example, naïve TH cell activation in the presence of the pro-inflammatory molecules, IFN-γ and IL-12, induces TH1 differentiation while IL-4 is a potent inducer of TH2 differentiation (Zhu et al., 2010). Importantly, induction of transcription factor (TF) expression by extracellular signals received by activated TH cells drives T cell differentiation (Kanno et al., 2012); TH1 differentiation is dependent on STAT1 activation and expression of the T-box TF Tbx21 (T-bet; Djuretic et al., 2007). Conversely, IL-4 signals activate STAT6 resulting in up-regulation of the TF Gata3 (Ansel et al., 2003). TH17 differentiation is associated with IL-6/IL-21 induced expression of the RORγT TF (Dong, 2008) and Treg differentiation with FoxP3 (reviewed in Josefowicz et al., 2012). Such is the importance of these TFs in directing naïve TH cell commitment to a specific lineage that they are used as definitive markers of TH subset differentiation (Figure 2).


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

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

CD4+ TH – cell subset differentiation. CD4+ T cells show remarkable plasticity and are able to differentiate into many different subsets based on the soluble molecules secreted during priming of the subsets by antigen presenting cells (APC), e.g., IL-12 for TH1 cells. The different subsets can be distinguished by the transcription factors that regulate and maintain their lineage-specific effector functions, e.g., T-bet for TH1 cells. The molecules secreted by these subsets, e.g., IFN-γ for TH1 cells, are finely tuned to control the pathogen that mediated the release of the specific molecules by the APC during activation of the TH0 cells into the various subsets.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: CD4+ TH – cell subset differentiation. CD4+ T cells show remarkable plasticity and are able to differentiate into many different subsets based on the soluble molecules secreted during priming of the subsets by antigen presenting cells (APC), e.g., IL-12 for TH1 cells. The different subsets can be distinguished by the transcription factors that regulate and maintain their lineage-specific effector functions, e.g., T-bet for TH1 cells. The molecules secreted by these subsets, e.g., IFN-γ for TH1 cells, are finely tuned to control the pathogen that mediated the release of the specific molecules by the APC during activation of the TH0 cells into the various subsets.
Mentions: An important feature of T cell immunity is the enormous proliferative potential and functional plasticity of naïve T cells. Acquisition of lineage-specific T cell effector functions is clearly linked to an extended proliferative response, suggesting that T cell activation engages a differentiation program that facilitates effector gene expression (Gett and Hodgkin, 1998; Lawrence and Braciale, 2004; Jenkins et al., 2008). An example of T cell functional plasticity is found after activation of naïve TH cells that have the potential to differentiate into distinct T cell subsets, largely defined by the soluble effector molecules they secrete (Figure 2; Zhu et al., 2010). The best characterized of these are the TH1 and TH2 subsets, however, other subsets include TH17, Tregs (regulatory T cells), TFH (follicular TH cells) and the more recently described TH9 cells (Figure 2). TH1 and TH2 T cells are best characterized by their capacity to secrete interferon-gamma (IFN-γ) and interleukin (IL)-4, respectively. The tailoring of TH cell responses into distinct functional lineages is a consequence of integration of multiple signals that are present during initial T cell activation (Figure 2). For example, naïve TH cell activation in the presence of the pro-inflammatory molecules, IFN-γ and IL-12, induces TH1 differentiation while IL-4 is a potent inducer of TH2 differentiation (Zhu et al., 2010). Importantly, induction of transcription factor (TF) expression by extracellular signals received by activated TH cells drives T cell differentiation (Kanno et al., 2012); TH1 differentiation is dependent on STAT1 activation and expression of the T-box TF Tbx21 (T-bet; Djuretic et al., 2007). Conversely, IL-4 signals activate STAT6 resulting in up-regulation of the TF Gata3 (Ansel et al., 2003). TH17 differentiation is associated with IL-6/IL-21 induced expression of the RORγT TF (Dong, 2008) and Treg differentiation with FoxP3 (reviewed in Josefowicz et al., 2012). Such is the importance of these TFs in directing naïve TH cell commitment to a specific lineage that they are used as definitive markers of TH subset differentiation (Figure 2).

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