Humanizing a CD28 signaling domain affects CD8 activation, exhaustion and stem-like precursors
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2025,
Номер
unknown
Опубликована: Март 13, 2025
CD28
ligation
provides
critical
signals
that
modulate
activated
T
cell
fate.
In
a
human
to
mouse
reverse-engineering
approach,
single
amino
acid
substitution
adjacent
the
C-terminal
proline-rich
domain
created
A210P
mice
with
enhanced
signaling.
experienced
pro-inflammatory
responses
superagonist
antibody,
analogous
severe
cytokine
storm
induced
in
clinical
trial,
striking
increase
of
CD8
cells.
acute
and
chronic
viral
infections,
early
activation
expansion
effector
cells
increased,
accelerated
exhaustion
infection.
Mechanistically,
JunB,
IL-2,
inhibitory
receptors
driven
by
MEK1/2.
Generation
stem-like
progenitor
(Tpex)
was
further
expanded
PD-L1
blockade
chronically-infected
mice.
Thus,
'humanized'
PYAP
reveal
key
roles
for
signaling
strength
activation,
accelerating
during
antigen
persistence,
while
promoting
sustaining
Tpex
A
'humanize'
enhances
response,
generation
infection
Язык: Английский
Reply to ‘Comment on: Glycogen synthase kinase 3 controls T-cell exhaustion by regulating NFAT activation’
Cellular and Molecular Immunology,
Год журнала:
2025,
Номер
unknown
Опубликована: Апрель 2, 2025
Язык: Английский
Disrupted priming within draining lymph nodes drives immune quiescence in gastric cancer
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2025,
Номер
unknown
Опубликована: Май 6, 2025
The
gastric
mucosa
is
characterized
by
continuous
innate
immune
surveillance
and
inflammatory
signaling,
yet
a
high
proportion
of
carcinomas
(GCs)
are
recalcitrant
to
immune-directed
therapies.
mechanisms
which
GCs
evade
adaptive
within
the
highly
antigenic
microenvironment
remains
unknown.
To
address
this,
we
collected
patient-matched
tumor
tissue,
distant
normal
metastasis,
draining
lymph
nodes
generate
large-scale
single-cell
profiling
dataset
from
64
patients
(n=179
samples,
>150,000
cells).
From
single
cell
analysis,
identified
two
distinct
sources
impaired
nodes.
First,
observed
that
significant
fraction
had
undergone
cytokine-driven
reprogramming,
leading
reduced
dendritic
homing
limited
T
priming.
Second,
cells
undergoing
successful
activation
exhibited
expansion
constrained
differentiation,
marked
expression
quiescence-associated
transcription
factor
Kruppel-like
Factor
2
(
KLF2
).
Overexpression
in
primary
both
their
differentiation
cytotoxic
capacity.
These
findings
implicate
priming
-dependent
quiescence
limiting
immunity
adenocarcinoma.
We
suggest
these
represent
an
emerging
model
for
silencing
tumors
developing
tissues
with
chronic
inflammation.
Язык: Английский
Aging Compromises Terminal Differentiation Program of Cytotoxic Effector Lineage and Promotes Exhaustion in CD8+ T Cells Responding to Coronavirus Infection
Aging Cell,
Год журнала:
2025,
Номер
unknown
Опубликована: Май 21, 2025
ABSTRACT
T
cell
aging
increases
the
risk
of
viral
infection‐related
morbidity
and
mortality
reduces
vaccine
efficacy
in
elderly.
A
major
hallmark
is
loss
quiescence
shift
toward
terminal
differentiation
during
homeostasis.
However,
how
impacts
program
virus‐specific
cells
infection
unclear.
Here,
a
murine
coronavirus
(MHV)
model
with
age‐associated
increased
mortality,
we
demonstrate
that
impairs,
instead
promoting,
CD8
+
cells.
Upon
infection,
CD4
old
mice
showed
marked
reduction
clonal
expansion
upregulation
immune
checkpoints
associated
exhaustion.
Bulk
single‐cell
transcriptomics
upregulated
exhaustion
transcriptional
TOX
shifted
myeloid
compartment
from
immunostimulatory
to
immunosuppressive
phenotype.
In
addition,
downregulated
terminally
differentiated
effector
diminished
CX3CR1
cytotoxic
lineage.
Mechanistically,
infected
aged
displayed
defects
inducing
transcription
factors
ZEB2
KLF2,
which
were
required
for
Together,
our
study
shows
impairs
promotes
responding
through
dysregulating
expression
lineage‐defining
factors.
Язык: Английский
Deciphering the deterministic role of TCR signaling in T cell fate determination
Frontiers in Immunology,
Год журнала:
2025,
Номер
16
Опубликована: Май 21, 2025
T
cell
receptor
(TCR)
signaling,
also
known
as
signal
1,
plays
a
crucial
role
in
the
activation
and
proliferation
of
cells.
The
question
whether
TCR
signaling
exerts
deterministic
fate
determination
is
an
area
active
investigation.
It
has
been
particularly
challenging
to
address
this
due
complexities
associated
with
genetic
manipulation
components,
which
often
disrupts
thymic
development
or
impairs
upon
engagement.
Recent
study
demonstrates
that
TCR-Lck/Fyn
axis
directly
induces
STAT3
phosphorylation
synergizes
pro-inflammatory
cytokines
optimize
during
Th17
differentiation.
Additionally,
TCR-Lck/Fyn-AKT/mTOR
negatively
regulates
Treg
In
CD8+
cells,
persistent
high-affinity
antigen
stimulation
drives
differentiation
along
exhaustion
pathway,
while
acute
infection
intermediate
levels
promote
into
effector
memory
although
underlying
mechanism
remains
be
fully
elucidated.
Collectively,
these
studies
provide
compelling
evidence
impact
on
fate.
This
review
summarizes
recent
advances
understanding
how
shapes
determination.
Язык: Английский
Enhancer-driven gene regulatory networks reveal transcription factors governing T cell adaptation and differentiation in the tumor microenvironment
Immunity,
Год журнала:
2025,
Номер
unknown
Опубликована: Май 1, 2025
Язык: Английский
Unravelling T cell exhaustion through co‐inhibitory receptors and its transformative role in cancer immunotherapy
Clinical and Translational Medicine,
Год журнала:
2025,
Номер
15(5)
Опубликована: Май 1, 2025
Язык: Английский
Restraining the killers: regulation of T cell quiescence
Trends in Immunology,
Год журнала:
2025,
Номер
unknown
Опубликована: Май 1, 2025
Язык: Английский
HDAC1 controls the generation and maintenance of effector-like CD8+ T cells during chronic viral infection
The Journal of Experimental Medicine,
Год журнала:
2025,
Номер
222(8)
Опубликована: Июнь 4, 2025
CD8+
T
cell
exhaustion
is
a
complex
process
involving
the
differentiation
of
persistently
activated
cells
into
functionally
distinct
subsets.
Here,
we
investigated
role
key
epigenetic
regulator
histone
deacetylase
1
(HDAC1)
in
exhausted
(Tex)
during
chronic
viral
infection.
We
uncovered
that
HDAC1
controls
generation
and
maintenance
effector-like
CX3CR1+
Tex
cell-intrinsic
manner.
Deletion
led
to
expansion
an
alternative
subset
characterized
by
high
expression
markers,
this
was
accompanied
elevated
viremia.
bound
facilitated
open
chromatin
state
signature
gene
loci
progenitor
cells,
thereby
priming
fate
specification
toward
subset.
Our
study
uncovers
selective
for
differentiation,
which
essential
controlling
load
Язык: Английский