The role of phosphoinositide-3-kinase in mast cell homing to the gastrointestinal tract.

Phosphoinositide-3-kinases (PI3Ks) are a family of lipid kinases essential in a variety of physiological reactions. A series of gene-targeted mice lacking different PI3Ks and related molecules has enabled us to understand their in vivo roles, particularly those of class IA members. Studies on knockout mice lacking class IA PI3Ks and knock-in mice expressing mutant forms of enzymes have revealed the importance of this class of PI3Ks in mast cell development in the gastrointestinal tract. Here we studied the role of the p85a regulatory subunit, the most abundantly expressed regulatory subunit of class IA PI3Ks, using p85a knockout mice. Development of mast cells in the gastrointestinal tract but not in the skin was severely impaired in mice lacking the p85a regulatory subunit. Stem cell factor (SCF)-mediated signalling functions including proliferative response and chemotactic activities were both impaired in p85a knockout mast cells, likely due to the mast cell deficiency. Mastocytosis upon Strongyloides veneZuelensis infection was also impaired in p85alpha knockout mice. Reconstitution with Th2-conditioned but not untreated bone marrow-derived mast cells (BMMCs) restored anti-bacterial immunity, indicating the importance of Th2 response in addition to the recruitment of mast cells in the control of nematode infection.