JoséMaríaRojo, Pilar Portolés
108
anti-‐CD3plusanti-‐CD28antibodiesunderneutral conditions IFN-‐
γ
-‐productionwas
highly sensitive to inhibitionof PI3K, at doses ten-‐fold lower than those needed to
inhibit proliferation, IL-‐2, or IL-‐10. The p110
δ
inhibitor IC87114 or the dual
p110
α
/
δ
inhibitor ETP-‐46321, were particularly effective, whereas inhibition by
A66, a p110
α
inhibitor was not asmarked (82). A differentially high inhibition of
IC87114 on IFN-‐
γ
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 p110
δ
inhibitor IC87114 that
naive cells. These resultspaved theway to showinhibitionby IC87114of anti-‐CD3
antibody-‐mediatedT cell activation or recall responses to vaccines in human cells
(87). In our experience, though, inhibition of cytokine production by CD4
+
blast
cells activationwith anti-‐CD3or anti-‐CD3plus anti-‐ICOS antibodieswas similar to
that observed inactivationof naiveCD4
+
Tcells (82).
In contrast, So et al. observed no significant effect of p110
α
inhibition by
A66 or MLN1117 on antigen-‐ or mitogen-‐ induced CD4
+
T cell proliferation, or
secretion of IL-‐2 and IFN-‐
γ
, although there was some inhibition of Akt
phosphorylation, and p110
α
inhibitors enhanced the clear but not complete
inhibition induced by IC87114 (81). A contribution of p110
α
to TCR and
costimulationsignaling isalsosuggested intheresponseof theCD4
+
Tcell lineD10
to anti-‐CD3 and anti-‐ICOS (14). In this system, we observed partial inhibition of
early Akt phosphorylation by the p110
α
inhibitor PIK-‐75 or by p110
α
silencing
(14). Intriguingly, whereas silencing p110
δ
or inhibition with IC87114 clearly
inhibited both Akt and Erk activation, p110
α
silencing markedly enhanced Erk
phosphorylation, suggesting that p110
α
might exert a negative control over some
p110
δ
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 affinitymaturation and differentiation of memory
cells. They characteristically express the surfacemolecules CXCR5, PD-‐1 and ICOS,
as well as the transcription suppressor Bcl6 (88). Although Tfh cells able of
producingdifferent antibody-‐promoting cytokines (IL-‐4, IL-‐10, IL-‐17, or IFN-‐
γ
) can
be found
in vivo
, IL-‐21 is themost 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 tobindPI3K, or inmice expressing the inactivep110
δ
D910A
kinase,
or inhibitionwith the p110
δ
inhibitor IC87114, taken together indicate that PI3K
p110
δ
is needed for Tfh differentiation and antibody production in a ICOS
dependent way; early TCR signaling or IL-‐21 production in differentiated Tfh is
alsopotentiatedby ICOS signaling and inhibitedby IC87114 (74,89). So et al. have
