A PIP₂-derived amplification loop fuels the sustained initiation of B cell activation

Lymphocytes have evolved sophisticated signaling amplification mechanisms to efficiently activate downstream signaling after detection of rare ligands in their microenvironment. B cell receptor microscopic clusters (BCR microclusters) are assembled on the plasma membrane and recruit signaling molecules for the initiation of lymphocyte signaling after antigen binding. We identified a signaling amplification loop derived from phosphatidylinositol 4,5-biphosphate (PIP₂) for the sustained B cell activation. Upon antigen recognition, PIP₂ was depleted by phospholipase C-γ2 (PLC-γ2) within the BCR microclusters and was regenerated by phosphatidic acid-dependent type I phosphatidylinositol 4-phosphate 5-kinase outside the BCR microclusters. The hydrolysis of PIP₂ inside the BCR microclusters induced a positive feedback mechanism for its synthesis outside the BCR microclusters. The falling gradient of PIP₂ across the boundary of BCR microclusters was important for the efficient formation of BCR microclusters. Our results identified a PIP₂-derived amplification loop that fuels the sustained initiation of B cell activation.