Role of PI3-kinase in the development and function of mast cells

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Role of class I_A PI3K in mast cell differentiation was examined using p85α-deficient mice. We have found that p85α-deficient mice selectively lack gastrointestinal and peritoneal mast cells whereas mast cells are readily found in other tissues such as skin under normal physiological conditions. We studied why p85α-deficient mice lack only gastrointestinal mast cells. We first examined the mast cell precursor frequency in the bone marrow, spleen and intestinal tract, by limiting dilution method. It was revealed that the precursor frequency in the intestine was less than 10% of wild type level whereas those of the bone marrow and spleen were unaffected compared to wild type mice. These results suggest that either the survival of progenitors and/or mature mast cell in the intestine or the migration of precursor cells to the intestine is impaired in p85α-deficient mice. We found that c-Kit signal is strongly impaired in p85α-deficient mast cells established from the bone marrow with IL-3 as proliferation and JNK activation in response to SCF was severely impaired in p85α-deficient cultured mast cells. We also examined the expression and function of integrins that are known to be important in cell migration. We found that expression of α4β7 integrin that is critical for cellular migration to the intestine was normal in p85α-deficient mast cells but the binding of α4β7 to its ligand, MAdCAM was significantly weaker than that of wild type mast cells. We conclude from these observations that the lack of gastrointestinal mast cells in p85α-deficient mice is due to the deficiency in both migration to and survival in the intestine.