An. Real. Acad. Farm. vol 80 nº 1 2014 - page 105

Class I phosphoinositide3-­‐kinases in immunity…
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9. CLASS IA AND IB IN IMMUNITY: LESSONS FROM GENETIC STUDIES: T
LYMPHOCYTES.In mice with hematopoietic cells lacking all p85α-­‐/-­‐ , p55α-­‐/-­‐ , p50α-­‐/-­‐
subunits the number and in vitro activation of T cells was largely normal (57);
mice lacking p85α subunits but not p55α or p50α had a similar phenotype (58).
No immunological defects have been described in mice lacking p55α or p50α subunits (59). Deletion of p85 β induced enhanced T-­‐lymphocyte responses (60),
however loss of p85 β impaired secondary T cell dependent antigen responses by
CD28-­‐mediated mechanisms (71). Conditional deletion of the class IA regulatory
subunits p85 α, p55α, p50α, andp85β in theTcell lineage (p55γ is undetectable in
T lymphocytes, J.M.R., unpublished data) resulted in normal T cell development
and Th1 differentiation. PI3K signals, antibody responses to T-­‐cell dependent
antigens, Th2, and Treg differentiation were impaired and the animals could
developanautoimmuneSjögren’s-­‐likesyndrome (72,73). As inB lymphocytes, loss
of p85α andp85β reducedbasal lymphocytemotility(61).
Inp110δ-­‐/-­‐ mice thenumberof qualityofT lymphocytesappearnormal; and
decreased responses toT-­‐cell dependent antibody responsesmight be largely due
to defects in the B cell compartment (64,65). Mice where wild type p110 δ is
substitutedby the catalytically inactive formp110δD910A were similar concerningB
lymphocytes, but in this case T cell antigen receptor (TCR) signaling was also
impaired;micedeveloped inflammatorybowel disease (66). Laterworkhas shown
that the p110δ subunit was key to ICOS-­‐mediated costimulation of effector
function in follicularhelperTcells (74)Mice with deleted p110γ subunits show altered differentiation in the
thymus, withdecreasedCD4+ numbers, impairedmigrationand survival ofmature
thymocyteaswell asmatureTcell activation(69,75)possiblybecausep110 γ binds
to and is activated by TCR ligation (24). However, other groups have found no
defects in CD4 + T cell signaling and proliferation but did show strong defects in
migration and trafficking in TCR transgenic mice (76,77); Martin et al. (78)
observednoeffect in themigrationand traffickingof naiveCD8 + Tcells, or in their
proliferation and activation migration. In contrast, migration of p110γ-­‐deficient
CD8 + effectorTcells inducedby inflammatorystimuliwas impaired(78).Double knockout mice (p110γ-­‐/-­‐p110δ-­‐/-­‐ ) deficient for both p110γ and
p110δ haveseveredefects inTcell differentiationas thymocytesareblocked inthe
DN3-­‐DN4 selection checkpoint of pre-­‐TCR signaling, with lowthymocyte numbers
and high apoptosis (79). Mice lacking p110γ and expressing the inactive mutant
p110δD910A (p110γ-­‐/-­‐ p110δD910A) have similarly strong defects in thymus
differentiation, but the few remaining T cells infiltrate the mucosas, show Th2-­‐
skewedresponsesandanomalouslyhigh IgE levels (70).