JoséMaríaRojo, Pilar Portolés
104
Inp110
δ
-‐/-‐
mice Ig in serumand thenumber ofmatureBcellswere low, B1
andmarginal zone B cellswere defective, yet T cell numbers and responseswere
normal. Responses to T-‐cell independent antigens are low and T-‐cell dependent
responses are severely impaired. B cell antigen receptor (BCR)-‐ and CD40-‐early
signals like calcium flux, activation of phospholipase C, Akt, and Btk, as well as
proliferationare impaired (64,65). Thesedata suggesteda specific, unique role for
p110
δ
inBcell signalingand function.
The results obtained inmice inwhichwild typep110
δ
is substitutedby the
catalytically inactive formp110
δ
D910A
were similar concerning B lymphocytes, but
in this case T cell antigen receptor (TCR) signaling was also impaired; mice
developed inflammatory bowel disease (66). Furthermore, p110
δ
D910A
mice had
high serum amounts of antigen-‐specific IgE antibody despite reduced levels of
other isotypes like IgM or IgG1; the same was observed in antigen-‐specific
responses or usingp110
δ
-‐specific inhibitors (67). This isdue to the specific roleof
p110
δ
-‐mediated signals inmaintaininghigh levels of the transcription repressorB
cell lymphoma 6 (BCL6) acting on the IgE promoter in germinal center (GC) B
lymphocytes (68), where B cells actively proliferate and are induced to produce
antibody responses of even higher affinity under the guidance of specialized
follicularhelperT(Tfh) cells.
Laterwork by the group of B. Alarcónhas shown that, indeedp110
δ
stably
binds to BCR and TCR ITAM containing chains through the Ras family protein
RRas2 (TC21) actively participating in tonic and ligand activation signaling (15).
Paradoxically, recent data show that patients with a spontaneous dominant gain-‐
of-‐function mutation of p110
δ
(p110
δ
E1021K
) suffer primary immunodeficiency
with lowIgG2 serumlevels, deficient responses tovaccines, lymphopenia andhigh
sensitivity to activation-‐induced cell death, despite elevated levels of
PtdIns(3,4,5)P
3
andphosphorylatedAkt (45).
Intriguingly, mice with double lymphocyte deletion of p110
α
and
p110
δ
D910A
indicates that p110
α
couldsubstitute forp110
δ
inagonist-‐independent
tonicBCRsignalingnecessary forBcell development fromBcell progenitors andB
cell survival; however p110
α
could not substitute for p110
δ
in agonist BCR
activation(63).
Both p110
δ
and p110
γ
catalytic subunits are highly expressed in
lymphocytes but not in other cell types that are not of hematopoietic origin.
However,micep110
γ
−/−
hadnoBcell defects but showaltereddifferentiation in the
thymus, withdecreasedCD4
+
numbers, impairedmigrationand survival ofmature
thymocyte as well as mature T cell activation, (69). Mice deficient in both p110
γ
and p110
δ
(p110
γ
-‐/-‐
p110
δ
D910A
) have a B cell phenotype similar to that of their
p110
γ
-‐sufficient counterparts (70).
