Class I phosphoinositide3-‐kinases in immunity…
109
recently described that IC87114 but not the p110
α
inhibitor MLN1117 inhibits
germinal center formation (81). Our own data indicates that ICOS enhances early
TCRactivating signals and IL-‐17Aproduction inTfh inap110
δ
-‐dependent fashion,
yet IL-‐21secretion is largely independent of ICOSand inhibitionof bothp110
δ
and
p110
α
isneededtoblock IL-‐21production(82).
ICOS and its PI3K associated activity intervene in yet another aspect of
germinal centerdevelopment, namely in the recruitment of activatedThelper 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 ligationof otherCD28 familymembers (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, Xuet al. found that recruitment of Tcells into follicleswasdependent on
thep110
δ
PI3Ksubunit (90),whereasusingaTh2Thelper cell linewehave found
that cell elongationwasdependent onp110
α
, rather thanp110
δ
(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 candifferentiate fromimmature precursors in the thymus
(tTreg cells), but also from mature CD4
+
lymphocytes in the periphery (pTreg
cells). A role for p110
δ
inTreg function is suggestedby data frommice transgenic
for the kinase-‐dead p110
δ
D910A
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. Unlikewild typemice, animals lacking p110
δ
canefficiently clear
Leishmania
infectionbecauseof strongdefects inTregnumber
andhoming (97). It is alsoparadoxical that theproportionof Tregdifferentiated in
vitro (iTreg) canbe fosteredby inhibitors of PI3KormTOR, yet this ismainly due
to p110
α
, as judged by the effect of inhibitors of p110
α
, p110
β
or p110
δ
(98,99).
In contrast, IL-‐2 dependent PI3K signals are necessary for Treg expansion, and
high PI3K signals due to PTENdeficiency 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-‐
restrictedCD8
+
populationof T lymphocytes that has a prime role in the response
against intracellular pathogens like viruses as well as in anti-‐tumor responses.
Thereare conflictingdataon the roleof PI3K inTCR-‐mediatedactivation inCD8
+
T
cells. According toNi et al., proliferationand inductionof cytotoxicactivity induced
byTCR/CD3andCD28 ligandswas not affectedby thePI3K inhibitorWortmannin
