Class I phosphoinositide3-‐kinases in immunity…
107
couldadd to thestronger inhibition inducedby thep110
δ
inhibitor IC87114on the
samephenomena, thatwasnot complete (81).
In vivo
, unlike administration of MLN1117, daily administration of a p110
δ
(IC87114) or a pan-‐PI3K inhibitor (GDC-‐0941) to immunized mice strongly
reducedmarginal 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 titerswere significantly enhanced by the p110
δ
inhibitor
IC87114 or the pan-‐PI3K inhibitor GDC-‐0941, but not by p110
α
inhibitors (81).
Our own results with a dual p110
α
/
δ
inhibitor (ETP-‐46321) administered after
initiation of antigen responses showed inhibition of antigen-‐specific serum IgG3,
butnot of IgM, IgG1, or IgG2bantibody(82).
As mentioned above, p110
α
inhibition did not affect B cell Akt and FOXO
signaling or survival induced by cytokines like IL-‐4 or BAFF, yet p110
δ
inhibitors,
pan-‐PI3K inhibitors, and to a lesser extent, also p110
β
inhibitors like TGX-‐221
producedsignificant results (80,81).
It has been observed that p110
δ
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 bemimicked
in vitro
or
in vivo
using p110
δ
-‐specific inhibitors like IC87114, or broad-‐spectrum PI3K inhibitors
like PIK-‐90 and PI-‐103, or GDC-‐0941, but not by p110
α
inhibitors likeMLN1117
(67,68,81).
11. CLASS IAAND IB PI3K IN IMMUNITY: LESSONS FROMSPECIFIC INHIBITORS
INTLYMPHOCYTES
Early data by Shi et al. using the PI3K inhibitorWortmannin indicated that
the role of PI3K in (CD4
+
) T lymphocyte activationwas 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 p110
δ
D910A
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 p110
δ
D910A
CD4
+
T lymphocyte into the Th1 (IFN-‐
γ
-‐producing) and Th2 (IL-‐4-‐producing) T
helper cell subsetswas also impaired. The p110
δ
inhibitor IC87114 inhibitedTh1
differentiation, butTh17differentiationwasevenmoresensitive to inhibition(86).
In contrast, we found that in cultures of naive CD4
+
T lymphocytes activatedwith
