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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

Kinetics of CD8+ T cell differentiation following viral infection. Shown is a typical CD8+ T cell response to a acute viral infection. Antigen presenting cells (APC) present viral antigens to CD8+ T cells. This initiates a program of clonal expansion and differentiation into effector CD8+ T cells capable of lineage-specific effector functions, including the ability to secrete pro-inflammatory (TNF-α, IFN-γ) and cytotoxic (perforin, granzyme) molecules. Following viral clearance, the CD8+ T cells undergo an extensive contraction phase, mediated by programed cell death. The remaining memory CD8+ T cells can persist in the host for years. In the event of a secondary exposure to the same virus, memory CD8+ T cells can rapidly expand and acquire effector functions.
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Figure 1: Kinetics of CD8+ T cell differentiation following viral infection. Shown is a typical CD8+ T cell response to a acute viral infection. Antigen presenting cells (APC) present viral antigens to CD8+ T cells. This initiates a program of clonal expansion and differentiation into effector CD8+ T cells capable of lineage-specific effector functions, including the ability to secrete pro-inflammatory (TNF-α, IFN-γ) and cytotoxic (perforin, granzyme) molecules. Following viral clearance, the CD8+ T cells undergo an extensive contraction phase, mediated by programed cell death. The remaining memory CD8+ T cells can persist in the host for years. In the event of a secondary exposure to the same virus, memory CD8+ T cells can rapidly expand and acquire effector functions.

Mentions: A cardinal feature of T cell immunity is the ability of naïve T cells to undergo a program of proliferation and functional differentiation upon activation, resulting in a large pool of cells, all capable of recognizing a particular pathogen, and that have acquired the immune functions necessary to control and eventually clear infection (Kaech et al., 2002; van Stipdonk et al., 2003; Figure 1). Once an infection is cleared, the majority of the expanded effector T cell population dies, leaving behind a small pool of long-lived cells that can recognize the same pathogen that triggered their initial activation (termed memory T cells; Marshall et al., 2001; Kaech et al., 2002; La Gruta et al., 2004). Importantly, these memory T cells produce a broader array of immune molecules than naïve cells, and in larger quantities, and unlike naïve cells, can respond to infection without the need for further differentiation (Lalvani et al., 1997; Agarwal and Rao, 1998; Oehen and Brduscha-Riem, 1998; Veiga-Fernandes et al., 2000). These features, combined with persistence at a higher frequency, enable memory T cells to respond more rapidly upon secondary infection, enabling earlier control and clearance of infection (Figure 1), and together, these features of memory T cells provide the basis of T cell-mediated immunity. Importantly, our understanding of the molecular factors that shape cell fate decisions and drive acquisition of T cell effector function is limited, and questions remaining to be determined include how a T cell decides to be a memory versus an effector cell, and what are the molecular mechanisms that enable stable maintenance of rapid effector function within memory T cells in the long-term? In this review we describe what we think are some of the more interesting and important studies addressing these and similar questions, with the aim of demonstrating the utility of the immune system as a tool for studying epigenetics and cellular differentiation. We start by discussing the diversity of T cells phenotypes, before describing our current understanding of how epigenetic regulation influences how these distinct functional T cell populations arise and are maintained.


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

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

Kinetics of CD8+ T cell differentiation following viral infection. Shown is a typical CD8+ T cell response to a acute viral infection. Antigen presenting cells (APC) present viral antigens to CD8+ T cells. This initiates a program of clonal expansion and differentiation into effector CD8+ T cells capable of lineage-specific effector functions, including the ability to secrete pro-inflammatory (TNF-α, IFN-γ) and cytotoxic (perforin, granzyme) molecules. Following viral clearance, the CD8+ T cells undergo an extensive contraction phase, mediated by programed cell death. The remaining memory CD8+ T cells can persist in the host for years. In the event of a secondary exposure to the same virus, memory CD8+ T cells can rapidly expand and acquire effector functions.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Kinetics of CD8+ T cell differentiation following viral infection. Shown is a typical CD8+ T cell response to a acute viral infection. Antigen presenting cells (APC) present viral antigens to CD8+ T cells. This initiates a program of clonal expansion and differentiation into effector CD8+ T cells capable of lineage-specific effector functions, including the ability to secrete pro-inflammatory (TNF-α, IFN-γ) and cytotoxic (perforin, granzyme) molecules. Following viral clearance, the CD8+ T cells undergo an extensive contraction phase, mediated by programed cell death. The remaining memory CD8+ T cells can persist in the host for years. In the event of a secondary exposure to the same virus, memory CD8+ T cells can rapidly expand and acquire effector functions.
Mentions: A cardinal feature of T cell immunity is the ability of naïve T cells to undergo a program of proliferation and functional differentiation upon activation, resulting in a large pool of cells, all capable of recognizing a particular pathogen, and that have acquired the immune functions necessary to control and eventually clear infection (Kaech et al., 2002; van Stipdonk et al., 2003; Figure 1). Once an infection is cleared, the majority of the expanded effector T cell population dies, leaving behind a small pool of long-lived cells that can recognize the same pathogen that triggered their initial activation (termed memory T cells; Marshall et al., 2001; Kaech et al., 2002; La Gruta et al., 2004). Importantly, these memory T cells produce a broader array of immune molecules than naïve cells, and in larger quantities, and unlike naïve cells, can respond to infection without the need for further differentiation (Lalvani et al., 1997; Agarwal and Rao, 1998; Oehen and Brduscha-Riem, 1998; Veiga-Fernandes et al., 2000). These features, combined with persistence at a higher frequency, enable memory T cells to respond more rapidly upon secondary infection, enabling earlier control and clearance of infection (Figure 1), and together, these features of memory T cells provide the basis of T cell-mediated immunity. Importantly, our understanding of the molecular factors that shape cell fate decisions and drive acquisition of T cell effector function is limited, and questions remaining to be determined include how a T cell decides to be a memory versus an effector cell, and what are the molecular mechanisms that enable stable maintenance of rapid effector function within memory T cells in the long-term? In this review we describe what we think are some of the more interesting and important studies addressing these and similar questions, with the aim of demonstrating the utility of the immune system as a tool for studying epigenetics and cellular differentiation. We start by discussing the diversity of T cells phenotypes, before describing our current understanding of how epigenetic regulation influences how these distinct functional T cell populations arise and are maintained.

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