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Rag defects and thymic stroma: lessons from animal models.
[omenn syndrome]
Thymocytes
and
thymic
epithelial
cells
(
TECs
)
cross-talk
is
essential
to
support
T
cell
development
and
preserve
thymic
architecture
and
maturation
of
TECs
and
Foxp
3
(
+
)
natural
regulatory
T
cells
.
Accordingly
,
disruption
of
thymic
lymphostromal
cross-talk
may
have
major
implications
on
the
thymic
mechanisms
that
govern
T
cell
tolerance
.
Several
genetic
defects
have
been
described
in
humans
that
affect
early
stages
of
T
cell
development
[
leading
to
severe
combined
immune
deficiency
(
SCID
)
]
or
late
stages
in
thymocyte
maturation
(
resulting
in
combined
immunodeficiency
)
.
Hypomorphic
mutations
in
SCID
-causing
genes
may
allow
for
generation
of
a
limited
pool
of
T
lymphocytes
with
a
restricted
repertoire
.
These
conditions
are
often
associated
with
infiltration
of
peripheral
tissues
by
activated
T
cells
and
immune
dysregulation
,
as
best
exemplified
by
Omenn
syndrome
(
OS
)
.
In
this
review
,
we
will
discuss
our
recent
findings
on
abnormalities
of
thymic
microenvironment
in
OS
with
a
special
focus
of
defective
maturation
of
TECs
,
altered
distribution
of
thymic
dendritic
cells
and
impairment
of
deletional
and
non-deletional
mechanisms
of
central
tolerance
.
Here
,
taking
advantage
of
mouse
models
of
OS
and
atypical
SCID
,
we
will
discuss
how
modifications
in
stromal
compartment
impact
and
shape
lymphocyte
differentiation
,
and
vice
versa
how
inefficient
T
cell
signaling
results
in
defective
stromal
maturation
.
These
findings
are
instrumental
to
understand
the
extent
to
which
novel
therapeutic
strategies
should
act
on
thymic
stroma
to
achieve
full
immune
reconstitution
.