The Journal of Experimental Medicine,
Год журнала:
2024,
Номер
221(9)
Опубликована: Июль 4, 2024
Coordination
of
cellular
metabolism
is
essential
for
optimal
T
cell
responses.
Here,
we
identify
cytosolic
acetyl-CoA
production
as
an
metabolic
node
CD8
function
in
vivo.
We
show
that
responses
to
infection
depend
on
derived
from
citrate
via
the
enzyme
ATP
lyase
(ACLY).
However,
ablation
ACLY
triggers
alternative,
acetate-dependent
pathway
mediated
by
acyl-CoA
synthetase
short-chain
family
member
2
(ACSS2).
Mechanistically,
acetate
fuels
both
TCA
cycle
and
production,
impacting
effector
responses,
histone
acetylation,
chromatin
accessibility
at
gene
loci.
When
functional,
ACSS2
not
required,
suggesting
obligate
substrate
function.
loss
renders
cells
dependent
(via
ACSS2)
maintain
Together,
coordinate
Nature Immunology,
Год журнала:
2024,
Номер
25(3), С. 552 - 561
Опубликована: Янв. 23, 2024
Abstract
The
steady
flow
of
lactic
acid
(LA)
from
tumor
cells
to
the
extracellular
space
via
monocarboxylate
transporter
symport
system
suppresses
antitumor
T
cell
immunity.
However,
LA
is
a
natural
energy
metabolite
that
can
be
oxidized
in
mitochondria
and
could
potentially
stimulate
cells.
Here
we
show
lactate-lowering
mood
stabilizer
lithium
carbonate
(LC)
inhibit
LA-mediated
CD8
+
immunosuppression.
Cytoplasmic
increased
pumping
protons
into
lysosomes.
LC
interfered
with
vacuolar
ATPase
block
lysosomal
acidification
rescue
diacylglycerol–PKCθ
signaling
facilitate
1
localization
mitochondrial
membranes,
thus
transporting
as
an
source
for
These
findings
indicate
targeting
metabolism
using
support
cancer
immunotherapy.
Cell Communication and Signaling,
Год журнала:
2024,
Номер
22(1)
Опубликована: Май 16, 2024
Abstract
Traditionally,
lactate
has
been
considered
a
‘waste
product’
of
cellular
metabolism.
Recent
findings
have
shown
that
is
substance
plays
an
indispensable
role
in
various
physiological
functions
and
contributes
to
energy
metabolism
signal
transduction
during
immune
inflammatory
responses.
The
discovery
lactylation
further
revealed
the
regulating
processes.
In
this
review,
we
comprehensively
summarize
paradoxical
characteristics
microenvironment
highlight
pivotal
roles
homeostasis,
shuttle,
(‘lactate
clock’)
acute
chronic
responses
from
molecular
perspective.
We
especially
focused
on
receptors
with
either
proinflammatory
or
anti-inflammatory
effects
complex
biological
signalling
pathways
investigated
dynamic
changes
cells
lactate-related
microenvironment.
Moreover,
reviewed
progress
use
as
therapeutic
target
for
response,
which
may
provide
new
perspective
treating
inflammation-related
diseases.
The Journal of Experimental Medicine,
Год журнала:
2024,
Номер
221(3)
Опубликована: Фев. 27, 2024
T
cells
are
integral
in
mediating
adaptive
immunity
to
infection,
autoimmunity,
and
cancer.
Upon
immune
challenge,
exit
from
a
quiescent
state,
followed
by
clonal
expansion
effector
differentiation.
These
processes
shaped
three
established
signals,
namely
antigen
stimulation
(Signal
1),
costimulation
2),
cytokines
3).
Emerging
findings
reveal
that
nutrients,
including
glucose,
amino
acids,
lipids,
crucial
regulators
of
cell
responses
interplay
with
Signals
1-3,
highlighting
nutrients
as
Signal
4
license
immunity.
Here,
we
first
summarize
the
functional
importance
underlying
mechanisms
nutrient
transport,
sensing,
signaling
orchestrating
activation
quiescence
exit.
We
also
discuss
roles
programming
differentiation
fitness
how
can
be
targeted
improve
disease
therapy.
Understanding
respond
microenvironments
will
provide
insights
into
context-dependent
functions
therapeutic
interventions.
