Inactivation of PI3Kγ and PI3Kδ distorts T-cell development and causes multiple organ inflammation

Mice lacking both the p110 gamma and p110 delta isoforms display severe impairment of thymocyte development. Here, we show that this phenotype is recapitulated in p110 gamma(-/-)/p110 delta(D910A/D910A) (p110 gamma(KO)delta(D910A)) mice where the p110 delta isoform has been inactivated by a point mutation. Moreover, we have examined the pathological consequences of the p110 gamma delta 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, p110 delta, but not p110 gamma, controls Th1 and Th2 cytokine secretion. Thus, the pathology in the p110 gamma delta-deficient mice is likely to be secondary to a developmental block in the thymus that leads to lymphopenia-associated inflammatory responses.