INSIGHTS | PERSPECTIVES
loci after T cell activation (10, 11). Recently,
characterization of repressive epigenetic
modifications during differentiation, as
described by Pace et al. and others (11–14),
have highlighted the importance of epigenetic silencing for proper Teff cell differentiation. Specifically, epigenetic silencing of
stem cell– and T cell memory–associated
genes in activated T cells permits efficient
Teff cell differentiation and function, such
that elimination of this activity results in
defective Teff cells (2, 11–14).
Investigations into the repressive chromatin landscape of CD8+ T cells have
focused on DNA methylation and trimethylation (me3) of specific lysine residues (K)
on the histone H3 (specifically, H3K27me3
and H3K9me3). The epigenetic “writer”
proteins responsible for adding these modifications include DNA methyltransferase
3A (DNMT3A), an enzyme responsible for
de novo DNA methylation, and the histone
methyltransferase enzymes enhancer of
zeste homolog 2 (EZH2) and SUV39H1 (10).
In mice, conditional ablation of Dnmt3a
(12) and Ezh2 (13) in T cells and germline
ablation of Suv39h1 (2) result in an altered
phenotypic composition of antigen-specific
CD8+ T cells after viral infection: Both the
proportion and number of responding
Teff cells are reduced and the frequency
of memory T cells are increased. In vitro
experiments using Ezh2-deficient T cells
suggest selective apoptosis within the Teff
cell population (14), which accounts for the
equal numbers of antigen-specific memory
cell subsets as well as the impaired func-
tional efficacy of CD8+ T cells after second-
ary viral challenge observed in Ezh2- and
Suv39h1-deficient mice (2, 13). Preserved
memory T cell formation is consistent with
the linear differentiation model that places
memory cell development before differ-
entiation into Teff cells. By contrast, in a
model that predicts that memory T cells
originate from Teff cells, one would expect
numbers of memory T cells to decrease as
well as Teff cells.
Transcriptional and epigenetic profiling
of Dnmt3a-, Ezh2-, and Suv39h1-deficient
Teff cells illustrates a common defect that is
responsible for impaired Teff cell differentia-
tion. Genes encoding master regulators of
the stem and memory cell state fail to ac-
quire repressive epigenetic modifications,
leading to aberrant gene expression and dif-
ferentiation (2, 12, 13). Therefore, epigenetic
repression of essential stem and memory
genes is required for full Teff cell differentia-
tion (see the figure). That Teff cell differen-
tiation is still possible with loss of any one
of these epigenetic writers illustrates the
functional redundancy in silencing stem
and memory genes, stressing the impor-
tance of this mechanism. This mirrors the
epigenetic silencing of developmental and
pluripotency genes during differentiation of
human embryonic stem cells (1) and further
highlights transcriptional silencing of stem
cell–associated genes as a hallmark of cel-
Understanding the mechanisms of epigenetic regulation of Teff cell differentiation
has considerable implications for multiple
fields, including cancer immunotherapy.
Less differentiated T cell subsets, such as
Tscm and Tcm cells, have enhanced proliferative potential and greater antitumor activity when transferred into both mice and
humans compared with the more differentiated T effector memory cell (Tem cell) and
Teff cell subsets. This is likely due to their
stem cell–like properties (4, 6). Because
the majority of cells currently used for T
cell–based cancer immunotherapy are Teff
cells, the epigenetic silencing of stem and
memory genes in these cells poses a considerable therapeutic roadblock. To reacquire
therapeutically beneficial stem cell–like
properties, Teff cells would need to be epigenetically reprogrammed. This can be experimentally accomplished, albeit inefficiently
(15). A greater understanding of the CD8+
T cell epigenome may therefore provide essential clues for how to unlock the potential
of highly differentiated, tumor-antigen–
specific T cells infiltrating tumors (4). Epigenetic modifying drugs may reverse the
repression of stem and memory genes in
differentiated T cells and improve T cell–
based immunotherapies. j
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4. L. Gattinoni et al. , Nat. Rev. Cancer12, 671 (2012).
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6. C. A. Klebanoff et al. , J. Clin. Invest.126, 318 (2016).
7. P. Graef et al., Immunity41, 116 (2014).
8. B. Youngblood et al., Nature 10.1038/nature25144(2017).
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10. A. T. Phan etal .,Immunity46, 714 (2017).
11. J. G. Crompton et al., Cell Mol. Immunol.13, 502 (2016).
12. B. H. Ladle et al. , Proc. Natl. Acad. Sci. U.S. A. 113, 10631
13. S. M. Gray et al., Immunity46, 596 (2017).
14. B. Kakaradov et al., Nat. Immunol. 18, 422 (2017).
15. K. Takahashi,S. Yamanaka, Cell 126,663(2006).
164 12 JANUARY 2018 • VOL 359 ISSUE 6372
Epigenetic state of
Tef TnTscm Tcm Tem
RNA Pol II
silencing of stem/
Shutting down stem and memory genes in CD8+ T cells
As cells differentiate, stem and memory genes pass through transitional epigenetic states, in which epigenetic
modifications associated with transcriptional activation, including H3K4me3 and H3K27ac, are lost via lysine
demethylases (KDMs) and histone deacetylases (HDACs). Conversely, repressive modifications such as DNA
methylation, H3K27me3, and H3K9me3 are gained because of epigenetic writers, including DNM T3A, EZH2 as
part of the Polycomb repressive complex 2 (PRC2), and SUV39H1. Not shown but occurring simultaneously
is the acquisition of activating epigenetic modifications at effector-associated genes during T cell differentiation.