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

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Science Immunology  17 Nov 2017:
Vol. 2, Issue 17, eaan0787
DOI: 10.1126/sciimmunol.aan0787

Sustaining B cell receptor signaling

It is well established that, upon activation, B cell receptors (BCRs) form microclusters that function as platforms to recruit intracellular molecules that relay signals downstream of the BCRs. Xu et al. have examined how the localization of phosphatidylinositol 4,5-biphosphate (PIP2) is regulated to sustain BCR signaling. Using state-of-the-art microscopy to examine the localization of PIP2 after BCR activation, the authors report that PIP2 is depleted within the BCR microclusters but is enriched outside the microclusters. Furthermore, by developing systems to manipulate PIP2 localization in this context, the authors found that maintenance of this PIP2 gradient is vital to sustain BCR signaling.


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.

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