Page 106 - 80_01

José
María
Rojo,
Pilar
Portolés

In
p110d-­-/-­-
mice
Ig
in
serum
and
the
number
of
mature
B
cells
were
low,
B1

and
marginal
zone
B
cells
were
defective,
yet
T
cell
numbers
and
responses
were

normal.
Responses
to
T-­-cell
independent
antigens
are
low
and
T-­-cell
dependent

responses
are
severely
impaired.
B
cell
antigen
receptor
(BCR)-­-
and
CD40-­-early

signals
like
calcium
flux,
activation
of
phospholipase
C,
Akt,
and
Btk,
as
well
as

proliferation
are
impaired
(64,65).
These
data
suggested
a
specific,
unique
role
for

p110d
in
B
cell
signaling
and
function.

The
results
obtained
in
mice
in
which
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).
Furthermore,
p110dD910A
mice
had

high
serum
amounts
of
antigen-­-specific
IgE
antibody
despite
reduced
levels
of

other
isotypes
like
IgM
or
IgG1;
the
same
was
observed
in
antigen-­-specific

responses
or
using
p110d-­-specific
inhibitors
(67).
This
is
due
to
the
specific
role
of

p110d-­-mediated
signals
in
maintaining
high
levels
of
the
transcription
repressor
B

cell
lymphoma
6
(BCL6)
acting
on
the
IgE
promoter
in
germinal
center
(GC)
B

lymphocytes
(68),
where
B
cells
actively
proliferate
and
are
induced
to
produce

antibody
responses
of
even
higher
affinity
under
the
guidance
of
specialized

follicular
helper
T
(Tfh)
cells.

Later
work
by
the
group
of
B.
Alarcón
has
shown
that,
indeed
p110d
stably

binds
to
BCR
and
TCR
ITAM
containing
chains
through
the
Ras
family
protein

RRas2
(TC21)
actively
participating
in
tonic
and
ligand
activation
signaling
(15).

Paradoxically,
recent
data
show
that
patients
with
a
spontaneous
dominant
gain-­-
of-­-function
mutation
of
p110d
(p110dE1021K)
suffer
primary
immunodeficiency

with
low
IgG2
serum
levels,
deficient
responses
to
vaccines,
lymphopenia
and
high

sensitivity
to
activation-­-induced
cell
death,
despite
elevated
levels
of

PtdIns(3,4,5)P3
and
phosphorylated
Akt
(45).

Intriguingly,
mice
with
double
lymphocyte
deletion
of
p110a
and

p110dD910A
indicates
that
p110a
could
substitute
for
p110d
in
agonist-­-independent

tonic
BCR
signaling
necessary
for
B
cell
development
from
B
cell
progenitors
and
B

cell
survival;
however
p110a
could
not
substitute
for
p110d
in
agonist
BCR

activation
(63).

Both
p110d
and
p110?
catalytic
subunits
are
highly
expressed
in

lymphocytes
but
not
in
other
cell
types
that
are
not
of
hematopoietic
origin.

However,
mice
p110?-/-
had
no
B
cell
defects
but
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).
Mice
deficient
in
both
p110?

and
p110d
(p110?-­-/-­-
p110dD910A)
have
a
B
cell
phenotype
similar
to
that
of
their

p110?-­-sufficient
counterparts
(70).

104