Inactivation of PI3Kgamma and PI3Kdelta distorts T-cell development and causes multiple organ inflammation.

Mice lacking both the p110γ and p110δ isoforms display severe impairment of thymocyte development. Here, we show that this phenotype is recapitulated in p110γ −/− /p110δ D910A/D910A (p110γ KO δ D910A ) mice where the p110δ isoform has been inactivated by a point mutation. Moreover, we have examined the pathological consequences of the p110γδ deficiency, which include profound T-cell lymphopenia, T-cell and eosinophil infiltration of mucosal organs, elevated IgE levels, and a skewing toward Th2 immune responses. Using small-molecule selective inhibitors, we demonstrated that in mature T cells, p110δ, but not p110γ, controls Th1 and Th2 cytokine secretion. Thus, the pathology in the p110γδ-deficient mice is likely to be secondary to a developmental block in the thymus that leads to lymphopenia-associated inflammatory responses.