Page 110 - 80_01

José
María
Rojo,
Pilar
Portolés

anti-­-CD3
plus
anti-­-CD28
antibodies
under
neutral
conditions
IFN-­-?-­-production
was

highly
sensitive
to
inhibition
of
PI3K,
at
doses
ten-­-fold
lower
than
those
needed
to

inhibit
proliferation,
IL-­-2,
or
IL-­-10.
The
p110d
inhibitor
IC87114
or
the
dual

p110a/d
inhibitor
ETP-­-46321,
were
particularly
effective,
whereas
inhibition
by

A66,
a
p110a
inhibitor
was
not
as
marked
(82).
A
differentially
high
inhibition
of

IC87114
on
IFN-­-?
production
versus
proliferation
was
also
observed
by

Okkenhaugh’s
group
(87).
Furthermore,
these
authors
observed
that
isolated

memory/effector
cells
were
more
sensitive
to
the
p110d
inhibitor
IC87114
that

naive
cells.
These
results
paved
the
way
to
show
inhibition
by
IC87114
of
anti-­-CD3

antibody-­-mediated
T
cell
activation
or
recall
responses
to
vaccines
in
human
cells

(87).
In
our
experience,
though,
inhibition
of
cytokine
production
by
CD4+
blast

cells
activation
with
anti-­-CD3
or
anti-­-CD3
plus
anti-­-ICOS
antibodies
was
similar
to

that
observed
in
activation
of
naive
CD4+
T
cells
(82).

In
contrast,
So
et
al.
observed
no
significant
effect
of
p110a
inhibition
by

A66
or
MLN1117
on
antigen-­-
or
mitogen-­-
induced
CD4+
T
cell
proliferation,
or

secretion
of
IL-­-2
and
IFN-­-?,
although
there
was
some
inhibition
of
Akt

phosphorylation,
and
p110a
inhibitors
enhanced
the
clear
but
not
complete

inhibition
induced
by
IC87114
(81).
A
contribution
of
p110a
to
TCR
and

costimulation
signaling
is
also
suggested
in
the
response
of
the
CD4+
T
cell
line
D10

to
anti-­-CD3
and
anti-­-ICOS
(14).
In
this
system,
we
observed
partial
inhibition
of

early
Akt
phosphorylation
by
the
p110a
inhibitor
PIK-­-75
or
by
p110a
silencing

(14).
Intriguingly,
whereas
silencing
p110d
or
inhibition
with
IC87114
clearly

inhibited
both
Akt
and
Erk
activation,
p110a
silencing
markedly
enhanced
Erk

phosphorylation,
suggesting
that
p110a
might
exert
a
negative
control
over
some

p110d
signals
(14).

Follicular
helper
T
cells
(Tfh)
are
particularly
and
functionally
very

important
to
the
development
germinal
centers
and
of
efficient
antibody

responses,
promoting
antibody
affinity
maturation
and
differentiation
of
memory

cells.
They
characteristically
express
the
surface
molecules
CXCR5,
PD-­-1
and
ICOS,

as
well
as
the
transcription
suppressor
Bcl6
(88).
Although
Tfh
cells
able
of

producing
different
antibody-­-promoting
cytokines
(IL-­-4,
IL-­-10,
IL-­-17,
or
IFN-­-?)
can

be
found
in
vivo,
IL-­-21
is
the
most
characteristic
cytokine
of
Tfh
cells.
Signaling
by

the
PI3K-­-binding
costimulators
CD28
and
ICOS
are
needed
for
efficient

development
of
Tfh
and
germinal
centers.
Work
with
mice
expressing
ICOS

mutants
unable
to
bind
PI3K,
or
in
mice
expressing
the
inactive
p110dD910A
kinase,

or
inhibition
with
the
p110d
inhibitor
IC87114,
taken
together
indicate
that
PI3K

p110d
is
needed
for
Tfh
differentiation
and
antibody
production
in
a
ICOS

dependent
way;
early
TCR
signaling
or
IL-­-21
production
in
differentiated
Tfh
is

also
potentiated
by
ICOS
signaling
and
inhibited
by
IC87114
(74,89).
So
et
al.
have

108