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Class
I
phosphoinositide
3-­-kinases
in
immunity…

recently
described
that
IC87114
but
not
the
p110a
inhibitor
MLN1117
inhibits

germinal
center
formation
(81).
Our
own
data
indicates
that
ICOS
enhances
early

TCR
activating
signals
and
IL-­-17A
production
in
Tfh
in
a
p110d-­-dependent
fashion,

yet
IL-­-21
secretion
is
largely
independent
of
ICOS
and
inhibition
of
both
p110d
and

p110a
is
needed
to
block
IL-­-21
production
(82).

ICOS
and
its
PI3K
associated
activity
intervene
in
yet
another
aspect
of

germinal
center
development,
namely
in
the
recruitment
of
activated
T
helper
cells

into
the
follicle.
ICOS
is
directly
involved
in
this
movement,
but
this
effect
is

independent
on
costimulation,
yet
is
dictated
by
the
interaction
of
ICOS
in
T
cells

and
its
ligand
ICOS-­-L
expressed
in
bystander
B
lymphocytes
in
a
PI3K-­-dependent

fashion
(90).
ICOS
ligation,
as
ligation
of
other
CD28
family
members
(CD28,
CTLA-­-
4/CD152)
can
induce
antigen-­-independent,
tyrosine
kinase
and
PI3K-­-dependent

changes
in
actin
cytoskeleton
and
cell
elongation
and
spreading
(14,91-­-95).

However,
Xu
et
al.
found
that
recruitment
of
T
cells
into
follicles
was
dependent
on

the
p110d
PI3K
subunit
(90),
whereas
using
a
Th2
T
helper
cell
line
we
have
found

that
cell
elongation
was
dependent
on
p110a,
rather
than
p110d
(14).

Another
functionally
important
T
cells
are
the
CD4+
regulatory
T
(Treg)

cells
that
express
the
transcription
factor
Foxp3
and
negatively
control
adaptive

immune
responses,
as
they
expand
during
normal
antigen
responses
to
help
in

their
termination.
They
can
differentiate
from
immature
precursors
in
the
thymus

(tTreg
cells),
but
also
from
mature
CD4+
lymphocytes
in
the
periphery
(pTreg

cells).
A
role
for
p110d
in
Treg
function
is
suggested
by
data
from
mice
transgenic

for
the
kinase-­-dead
p110dD910A
mutation.
These
mice
have
reduced
numbers
of

Treg
cells
with
reduced
suppressor
capability
in
vitro
and
in
vivo
(96).

Paradoxically,
this
deficit
in
Treg
function
can
help
in
producing
efficient
anti-­-
parasite
responses
in
certain
cases.
Unlike
wild
type
mice,
animals
lacking
p110d

can
efficiently
clear
Leishmania
infection
because
of
strong
defects
in
Treg
number

and
homing
(97).
It
is
also
paradoxical
that
the
proportion
of
Treg
differentiated
in

vitro
(iTreg)
can
be
fostered
by
inhibitors
of
PI3K
or
mTOR,
yet
this
is
mainly
due

to
p110a,
as
judged
by
the
effect
of
inhibitors
of
p110a,
p110ß
or
p110d
(98,99).

In
contrast,
IL-­-2
dependent
PI3K
signals
are
necessary
for
Treg
expansion,
and

high
PI3K
signals
due
to
PTEN
deficiency
do
not
affect
Treg
function
in
vitro
or
in

vivo
(100).

The
last
T
cell
subset
to
be
considered
is
the
cytotoxic,
MHC
class
I-­-
restricted
CD8+
population
of
T
lymphocytes
that
has
a
prime
role
in
the
response

against
intracellular
pathogens
like
viruses
as
well
as
in
anti-­-tumor
responses.

There
are
conflicting
data
on
the
role
of
PI3K
in
TCR-­-mediated
activation
in
CD8+
T

cells.
According
to
Ni
et
al.,
proliferation
and
induction
of
cytotoxic
activity
induced

by
TCR/CD3
and
CD28
ligands
was
not
affected
by
the
PI3K
inhibitor
Wortmannin

109