plied to a real material, taking into account
its structure and chemical composition, allowing for quantitative calculations of the
properties of electronic excitations.
These calculations are, however, far easier
for the single excitations associated with
ARPES or STM than for the combined particle-hole excitations, as measured in INS. In
recent years, however, and with the progress
of numerical algorithms, the calculation of
these combined excitation spectra from dynamical mean field theory has become possible (10–14). Park, who led the theory team
in Goremychkin et al., pioneered the development and application of such calculations
to real materials such as CePd3, along with
Haule and Kotliar (12). This effort is itself
a remarkable achievement because the combined excitations observed by INS are hard
to deconvolute in terms of single excitations.
Thus, theory played a key role in explaining
the experimental results, and the agreement
between the theoretical calculations and the
observed INS spectra was indeed excellent.
This study demonstrates once more how
instrumental progress is crucial to advance
fundamental science, especially large experimental facilities such as neutron sources,
and that theoretical and computational efforts are necessary to take full advantage of
the new results generated. j
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“This collective state at low
temperature is the host to
coherent excitations, which
have an entangled character
that mixes together 4f and
in T cell differentiation
Epigenetic repression is required
for the generation of CD8+ effector T cells
By Amanda N. Henning,1,2 Christopher A.
Klebanoff,3,4 Nicholas P. Restifo1,2
Functional diversity in multicellular organisms is achieved through the dif- ferentiation of stem cells. During this process, stem cells must retain both the capacity for self-renewal and the ability to differentiate into highly specialized cell types to produce a diverse array of tissues, each with distinct functions
and organization. This plasticity is achieved
through alterations to the epigenome, heritable and reversible modifications to DNA
and histones that affect chromatin structure
and gene transcription without altering the
DNA sequence itself. Alterations to the epigenome enable cell type–specific transcriptional control that can change dynamically
over the life of a cell. Such flexibility and
responsiveness are instrumental in directing gene expression changes throughout
cellular differentiation and lineage specification. The acquisition of more specialized
functions during differentiation requires
not only that the epigenome turn “on” genes
involved in lineage commitment, it also necessitates that genes associated with stemness are simultaneously turned “off” (1). On
page 177 of this issue, Pace et al. (2) demonstrate that this phenomenon exists in CD8+
T cells, in which epigenetic repression of
stemness-associated genes by the histone
methyltransferase SUV39H1 is required for
T cell effector differentiation. Understanding these mechanisms addresses important
questions in immunology and is applicable
to cancer immunotherapy.
The CD8+ T lymphocyte compartment of
the adaptive immune system has emerged
as a model for developmental biology in
adult mammalian cells owing to its remark-
able degree of functional plasticity (3).
CD8+ T cells can rapidly differentiate from
a quiescent, long-lived memory state into
an effector state characterized by short-
lived cytotoxicity toward cancer cells or
cells infected with intracellular pathogens
(4). Multiple differentiation models have
been proposed to account for the observed
changes in CD8+ T cell subsets during an
immune response. The linear differentia-
tion model places effector T cells (Teff cells)
at the end of the differentiation process af-
ter the development of multiple intermedi-
ary memory T cell subsets (3). Specialized
memory T cells, including the relatively
rare T memory stem cells (Tscm cells) and
the more common central memory T cells
(Tcm cells), have characteristics associated
with conventional stem cells. This includes
enhanced self-renewal, which is essential
for maintaining long-term immunologi-
cal memory, and the ability to reconstitute
other CD8+ T cell subsets, which maintains
the functional diversity of the CD8+ T cell
compartment (5–7). Tscm cells have en-
hanced stem cell–like capabilities, whereas
Tcm cells are poised to rapidly initiate an ef-
fector response. With further T cell activa-
tion, memory subsets can differentiate into
Teff cells followed by terminal differentia-
tion, functional senescence, and ultimately
apoptosis (cell death). An alternative model
suggests that naïve T cells (Tn cells) differen-
tiate into Teff cells immediately after activa-
tion, with “dedifferentiation” into memory
cells occurring after pathogen clearance (8).
Because the dedifferentiation of lineage-re-
stricted cells rarely occurs in nature outside
of cancer formation (9), we and others (7)
feel that the linear differentiation model is
more consistent with typical patterns of cel-
CD8+ T cell subsets can be partitioned on
the basis of distinct patterns of gene expression. Multiple subset-specific transcription
factors regulate gene expression throughout differentiation (4). Although transcription factors are critical mediators of
gene expression programs, their activity is
largely dependent on epigenetic modifications, the profiles of which can also be used
to distinguish T cell subsets (10). Indeed,
activating epigenetic modifications are progressively gained at Teff cell–associated gene
1Center for Cell-Based Therapy, National Cancer Institute
(NCI), National Institutes of Health (NIH), Bethesda, MD
20892, USA. 2Center for Cancer Research, NCI, NIH, Bethesda,
MD 20892, USA. 3Center for Cell Engineering and Department
of Medicine, Memorial Sloan Kettering Cancer Center
(MSKCC), Ne w York, NY 10065, USA. 4Parker Institute for
Cancer Immunotherapy, MSKCC, New York, N Y 10065, USA.
12 JANUARY 2018 • VOL 359 ISSUE 6372 163