JoséMaríaRojo, Pilar Portolés
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1. INTRODUCTION
This review focuses on the use and possible applications of
phosphoinositide-‐3 kinase (PI3K)-‐specific inhibitors to modulate immune
responses,withanemphasisonT lymphocyte-‐dependent adaptiveresponses.
Phosphoinositide-‐3 kinases (PI3Ks) are enzymes that phosphorylate the
OH-‐ group at the D3-‐position of the inositol ring of inositol-‐containing lipids
(PtdIns) located in inner leaflet of membrane bilayers. In this way, they generate
intracellularphosphorylated inositol lipids (PtdInsP) that serve toanchor cytosolic
enzymes facilitating interaction with their substrates and/or their activation,
initiating different cell signaling cascades (Figure 1) (reviewed in (1-‐5)). This is
mediated by membrane translocation of different effector proteins that possess
domains, like the Pleckstrin homology domain (PH), the Phox homology domain
(PX) or theFYVEdomain, specific fordistinct phosphorylated inositides (Figure1).
These effector proteins are involved in the regulation of many essential cell
functions including cell survival, growth, and proliferation. Not surprisingly,
different signals essential to the function of cells of the immune system activate
PI3Kactivity. For instance, in lymphocytes PI3Kactivity is enhancedupon antigen
activation, engagement of costimulatory molecules, binding of cytokines or
quimiokines to their receptors, or integrin-‐mediated adhesion. Thus, PI3Ks are
prime targets for immunomodulatorystrategies.
Differences in protein structure, regulation of activity, and lipid substrate
preference define three different classes of PI3K, namely class I, class II and class
III PI3K(Figure1, 2). Inmammals thereareeight different PI3K isoforms. Of them,
four are class I PI3Ks (p110α, p110β, p110γ and p110δ), three belong to class II
PI3K(PI3K-‐C2α, PI3K-‐C2β, PI3K-‐C2γ) and thevacuolar sortingprotein34 (VPS34)
is theonlyclass III PI3K. Class I arePI3Kinases specific forPtdIns(4,5)P
2
andplaya
major role in signal transduction induced by receptors that activate protein
tyrosinekinases (class IAPI3K) or by receptors coupled to small GTPases (class IB
PI3K). Class II and III PI3Kinases phosphorylate PtdIns. Class II have a role in
signal transduction, butmanyaspects of their biologyarenotwell known; Class III
havearole invesicle trafficking.
