Phosphatidylinositol 3-kinases (PI3Ks), a family of p85–p110 heterodimeric lipid kinases, are important regulators of cell signalling. But, do the three isoforms of the catalytic p110 subunit (p110α, -β and -δ) have distinct biological roles? Okkenhaug and colleagues report in Science that B-cell receptor (BCR) and T-cell receptor (TCR) signalling is impaired in p110δ-mutant mice, which indicates that p110δ has a specific role in immunity.

Previous studies of the PI3Ks have been complicated by the fact that altering the level of expression of one subunit can affect the expression of the others. To avoid this, rather than generating p110δ-knockouts, the authors generated mice that express an inactivated, point-mutated p110δ protein (p110δD910A) at normal levels.

B-cell development was affected in these mice: their bone marrow contained reduced numbers of B-cell progenitors; the ratio of pre- to pro-B cells was altered; their spleens contained 50% fewer B cells than in wildtype mice; and marginal-zone B cells were undetectable. T-cell development was normal with respect to CD4/CD8 profiles, but the level of expression of CD44 by peripheral T cells (a marker that is associated with a memory, rather than naive, phenotype) was reduced.

In addition to this role in the development of B and T cells, further experiments showed that p110δ is required for the function of these cells. BCR signalling and B-cell proliferation in response to anti-IgM antibodies was reduced, and the p110δ D910A mice had lower levels of serum immunoglobulin and defective humoral responses, and they failed to form germinal centres in the spleen. TCR signalling and T-cell proliferation in response to anti-CD3 antibodies or antigen was also defective. Taken together, these results indicate that p110δ has a unique role in antigen-receptor signalling.

The p110δ D910A mice also developed a mild inflammatory bowel disease (IBD). This is interesting because the human p110δ gene ( PI3KCD ) maps to the IBD7 susceptibility locus, and, as the authors propose, further investigations might show that PI3KCD is a human IBD-susceptibility gene.