Page 107 - 80_01

Class
I
phosphoinositide
3-­-kinases
in
immunity…

9.
CLASS
IA
AND
IB
IN
IMMUNITY:
LESSONS
FROM
GENETIC
STUDIES:
T

LYMPHOCYTES.

In
mice
with
hematopoietic
cells
lacking
all
p85a-­-/-­-,
p55a-­-/-­-,
p50a-­-/-­-

subunits
the
number
and
in
vitro
activation
of
T
cells
was
largely
normal
(57);

mice
lacking
p85a
subunits
but
not
p55a
or
p50a
had
a
similar
phenotype
(58).

No
immunological
defects
have
been
described
in
mice
lacking
p55a
or
p50a

subunits
(59).
Deletion
of
p85ß
induced
enhanced
T-­-lymphocyte
responses
(60),

however
loss
of
p85ß
impaired
secondary
T
cell
dependent
antigen
responses
by

CD28-­-mediated
mechanisms
(71).
Conditional
deletion
of
the
class
IA
regulatory

subunits
p85a,
p55a,
p50a,
and
p85ß
in
the
T
cell
lineage
(p55?
is
undetectable
in

T
lymphocytes,
J.M.R.,
unpublished
data)
resulted
in
normal
T
cell
development

and
Th1
differentiation.
PI3K
signals,
antibody
responses
to
T-­-cell
dependent

antigens,
Th2,
and
Treg
differentiation
were
impaired
and
the
animals
could

develop
an
autoimmune
Sjögren’s-­-like
syndrome
(72,73).
As
in
B
lymphocytes,
loss

of
p85a
and
p85ß
reduced
basal
lymphocyte
motility
(61).

In
p110d-­-/-­-
mice
the
number
of
quality
of
T
lymphocytes
appear
normal;
and

decreased
responses
to
T-­-cell
dependent
antibody
responses
might
be
largely
due

to
defects
in
the
B
cell
compartment
(64,65).
Mice
where
wild
type
p110d
is

substituted
by
the
catalytically
inactive
form
p110dD910A
were
similar
concerning
B

lymphocytes,
but
in
this
case
T
cell
antigen
receptor
(TCR)
signaling
was
also

impaired;
mice
developed
inflammatory
bowel
disease
(66).
Later
work
has
shown

that
the
p110d
subunit
was
key
to
ICOS-­-mediated
costimulation
of
effector

function
in
follicular
helper
T
cells
(74)

Mice
with
deleted
p110?
subunits
show
altered
differentiation
in
the

thymus,
with
decreased
CD4+
numbers,
impaired
migration
and
survival
of
mature

thymocyte
as
well
as
mature
T
cell
activation
(69,75)
possibly
because
p110?
binds

to
and
is
activated
by
TCR
ligation
(24).
However,
other
groups
have
found
no

defects
in
CD4+
T
cell
signaling
and
proliferation
but
did
show
strong
defects
in

migration
and
trafficking
in
TCR
transgenic
mice
(76,77);
Martin
et
al.
(78)

observed
no
effect
in
the
migration
and
trafficking
of
naive
CD8+
T
cells,
or
in
their

proliferation
and
activation
migration.
In
contrast,
migration
of
p110?-­-deficient

CD8+
effector
T
cells
induced
by
inflammatory
stimuli
was
impaired
(78).

Double
knockout
mice
(p110?-­-/-­-p110d-­-/-­-)
deficient
for
both
p110?
and

p110d
have
severe
defects
in
T
cell
differentiation
as
thymocytes
are
blocked
in
the

DN3-­-DN4
selection
checkpoint
of
pre-­-TCR
signaling,
with
low
thymocyte
numbers

and
high
apoptosis
(79).
Mice
lacking
p110?
and
expressing
the
inactive
mutant

p110dD910A
(p110?-­-/-­-
p110dD910A)
have
similarly
strong
defects
in
thymus

differentiation,
but
the
few
remaining
T
cells
infiltrate
the
mucosas,
show
Th2-­-
skewed
responses
and
anomalously
high
IgE
levels
(70).

105