Page 109 - 80_01

Class
I
phosphoinositide
3-­-kinases
in
immunity…

could
add
to
the
stronger
inhibition
induced
by
the
p110d
inhibitor
IC87114
on
the

same
phenomena,
that
was
not
complete
(81).

In
vivo,
unlike
administration
of
MLN1117,
daily
administration
of
a
p110d

(IC87114)
or
a
pan-­-PI3K
inhibitor
(GDC-­-0941)
to
immunized
mice
strongly

reduced
marginal
zone
B
cell
numbers
in
the
spleen;
GDC-­-0941
also
reduced
the

number
of
germinal
centers
(81).
Despite
these
effects,
antigen
specific
IgM,
IgG1

titers
in
the
serum
of
immunized
mice
was
not
significantly
lower
or
were

elevated,
and
in
fact
IgE
titers
were
significantly
enhanced
by
the
p110d
inhibitor

IC87114
or
the
pan-­-PI3K
inhibitor
GDC-­-0941,
but
not
by
p110a
inhibitors
(81).

Our
own
results
with
a
dual
p110a/d
inhibitor
(ETP-­-46321)
administered
after

initiation
of
antigen
responses
showed
inhibition
of
antigen-­-specific
serum
IgG3,

but
not
of
IgM,
IgG1,
or
IgG2b
antibody
(82).

As
mentioned
above,
p110a
inhibition
did
not
affect
B
cell
Akt
and
FOXO

signaling
or
survival
induced
by
cytokines
like
IL-­-4
or
BAFF,
yet
p110d
inhibitors,

pan-­-PI3K
inhibitors,
and
to
a
lesser
extent,
also
p110ß
inhibitors
like
TGX-­-221

produced
significant
results
(80,81).

It
has
been
observed
that
p110d
signals
play
an
essential
role
in
inhibiting

excess
IgE
production
by
maintaining
the
levels
of
the
BCL6
that
negatively

controls
the
IgG1
to
IgE
switch.
These
effects
can
be
mimicked
in
vitro
or
in
vivo

using
p110d-­-specific
inhibitors
like
IC87114,
or
broad-­-spectrum
PI3K
inhibitors

like
PIK-­-90
and
PI-­-103,
or
GDC-­-0941,
but
not
by

p110a
inhibitors
like
MLN1117

(67,68,81).

11.
CLASS
IA
AND
IB
PI3K
IN
IMMUNITY:
LESSONS
FROM
SPECIFIC
INHIBITORS

IN
T
LYMPHOCYTES

Early
data
by
Shi
et
al.
using
the
PI3K
inhibitor
Wortmannin
indicated
that

the
role
of
PI3K
in
(CD4+)
T
lymphocyte
activation
was
dependent
on
the
stimulus

used.
Production
of
IL-­-2
by
the
surrogate
antigen
activation
anti-­-CD3
antibodies

plus
CD28
costimulus
seemed
largely
PI3K-­-independent,
whereas
activation
and

Th2
differentiation
of
the
same
cells
by
peptide
antigen
and
antigen-­-presenting

cells
was
clearly
inhibited
by
Wortmannin
(83).
Although
the
specificity
of

Wortmannin
for
PI3K
has
been
questioned
(see,
i.e.
(9,84)),
later
studies
by

Okkenhaugh
et
al.
in
mice
expressing
the
inactive
p110dD910A
mutant
also
found

that
antigen
activation,
rather
that
activation
by
anti-­-CD3
plus
anti-­-CD28,
was

impaired
in
the
mutant
mice(66,85).
Furthermore,
differentiation
of
p110dD910A

CD4+
T
lymphocyte
into
the
Th1
(IFN-­-?-­-producing)
and
Th2
(IL-­-4-­-producing)
T

helper
cell
subsets
was
also
impaired.
The
p110d
inhibitor
IC87114
inhibited
Th1

differentiation,
but
Th17
differentiation
was
even
more
sensitive
to
inhibition
(86).

In
contrast,
we
found
that
in
cultures
of
naive
CD4+
T
lymphocytes
activated
with

107