INSIGHTS | PERSPECTIVES
Can T cells be
to fight back?
The transcriptional network
becomes less malleable in
persistently activated T cells
By Stephen J. Turner and Brendan E. Russ
When T cells are persistently acti- vated by antigen, such as during chronic infection or in cancer, they can become functionally incapable of performing their effector ac- tivities, a condition called T cell
exhaustion. Exhaustion therefore thwarts
optimal immune control of infection and tumors. There is a need to learn more about the
molecular factors that drive T cell exhaustion
and just how malleable T cell immunity is
once exhaustion is established. On pages
1165 and 1160 of this issue, Sen et al. (1) and
Pauken et al. (2), respectively, demonstrate
that T cell exhaustion represents a stable
differentiation state, underpinned by the
apparently irreversible installation of an
exhaustion-specific genetic landscape. This
implies that perhaps in a majority of cases
of persistent immune activation, T cells are
too exhausted to fight back against cancer or
Cancer immunotherapy aims to commandeer the T cell arm of our immune system
to detect and remove tumors (3, 4). This
stems from observations that during an
immune response, the immune system limits
collateral damage to host tissues by engaging
inhibitory pathways that suppress T cell
function (5, 6). Unfortunately, many tumors
engage these same inhibitory checkpoints
to evade antitumor immunity (7). Given that
several of these immune checkpoints are
mediated by receptor–ligand signaling, they
have proven amenable to administration
of antibodies that interrupt ligand binding
(called “checkpoint blockade”), allowing T
cell reactivation and tumor targeting (3, 4).
Indeed, checkpoint blockade has generated
excitement owing to some spectacular
clinical results, including complete tumor
regression and remission in patients with
Department of Microbiology, Biomedical
Discovery Institute, Monash University, Australia.
weeks of a valine-restricted diet, long-term
repopulating HSCs from the mouse bone
marrow are lost. After only 2 weeks of valine
starvation, a sufficient number of HSC niches
become vacant and allow chemoirradiation-free engraftment of transplanted donor-HSCs
in congenic mice.
Because myeloablative chemoirradia-
tion has severe side effects (infertility, poor
overall health, premature aging), there is a
medical need for alternative stem cell trans-
plantation approaches. Along these lines,
the short-term dietary valine restriction is
comparatively well tolerated and, besides
the desired hypocellularity in hematopoi-
etic tissues, results only in decreased num-
bers of hair follicles and increased brown
fat tissue in mice. Importantly, and in con-
trast to chemoirradiation, valine-restricted
mice remained fertile, showed good overall
health, and exhibited no obvious signs of
premature aging. However, fast refeeding
with a valine-containing diet caused the
death of about 50% of mice owing to the de-
velopment of a typical refeeding syndrome
(12). These complications could be avoided
by applying a gradual change in the valine-
restricted diet. Nonetheless, concerns about
the safety of this strategy remain. Previously,
it was shown that reduced expression of the
KIT receptor tyrosine kinase (whose ligand
is stem cell factor) was also sufficient to al-
low stem cell engraftment (13, 14). It would
thus be interesting to examine whether the
effects of valine depletion on HSCs are me-
diated by decreasing KIT expression.
Taya et al. also observed that human
HSCs cultured in vitro or analyzed in xeno-grafts depended on valine and, in contrast to
mice, also on leucine. Valine and leucine are
branched-chain amino acids that, when metabolized, influence a-ketoglutarate (aKG)
concentrations. aKG controls embryonic
stem cell pluripotency by acting as a substrate for DNA- and histone-demethylases
that control the cell’s epigenetic state (15).
More studies are needed to explore such a
mechanism and the molecular processes by
which valine and leucine control HSC maintenance. This should help to unravel how
our daily diet controls stem cell function and
thus our regenerative organ systems. j
1. D. Walter et al., Nature 520, 549 (2015).
2. K. Ito, T. Suda, Nat. Rev. Mol. Cell Biol. 15, 243 (2014).
3. A. Trumpp et al., Nat. Rev. Immunol. 10,201(2010).
4. K. Ito etal.,Science354, 1156 (2016).
5. Y. Taya et al., Science 354, 1152(2016).
6. A. Wilson et al., Cell135, 1118 (2008).
7 . R. Yamamoto et al., Cell 154, 1112 (2013).
8. F. Arai et al., Cell 118, 149 (2004).
9. J. Y. Chen etal .,Nature 530, 223 (2016).
10. K.Ito etal.,Nat.Med.18,1350(2012).
11. C. Mantel et al ., Cell Cycle 9, 2008 (2010).
12. H. M. Mehanna et al., BMJ336, 1495 (2008).
13. A. Chhabraetal .,Sci. Transl.Med. 8, 351ra105 (2016).
14. K. N. Cosgun et al ., Cell Stem Cell 15, 227 (2014).
15. B. W. Carey et al ., Nature 518, 413 (2015).
Activation of mitophagy
Vacant HSC niches created
HSC marker: TIE2
Increased stem cell activity
niches Activation of PPAR;-FAO pathway
PPAR; agonist treatment
In vivo In vitro
Metabolic characteristics of HSCs
Activation of mitophagy through a pathway that activates fatty acid oxidation (FAO) promotes TIE2+ HSC
expansion by enhanced symmetric divisions. Valine is required for HSC maintenance, and lack of dietary valine
empties bone marrow HSC niches, enabling chemoirradiation-free donor-HSC engraftment.