p110[gamma] and p110[delta] isoforms of phosphoinositide 3-kinase differentially regulate natural killer cell migration in health and disease

The mechanisms that regulate NK cell trafficking are unclear. Phosphoinositide-3 kinases (PI3K) control cell motility and the p110[gamma], and p110[delta] isoforms are mostly expressed in leukocytes, where they transduce signals downstream of G protein coupled receptors (GPCR) or tyrosine kinase receptors, respectively. Here, we set out to determine the relative contribution of p110[gamma], and p110[delta] to NK cell migration in mice. Using a combination of single-cell imaging analysis of transgenic cells reporting on PI3K activity in real time and small molecule inhibitors of p110[gamma], and p110[delta], we show here that the tyrosine-kinase coupled p110[delta] is linked to GPCR signaling and, depending on the GPCR, may even be preferentially activated over p1107. Using gene-targeted mice, we showed that both isoforms were essential for NK cell chemotaxis to CXCL12 and to CCL3 and, in vivo, for normal NK cell migration during pregnancy and to the inflamed peritoneum. By contrast, only p110[delta] was indispensable for chemotaxis to SIP and CXCL10 and for NK cell distribution throughout lymphoid and nonlymphoid tissues and for extravasation to tumors. These results implicate p110[delta] downstream of GPCRs in NK cells and highlight its nonredundant role as a key regulator of NK cell trafficking in health and disease. cell signaling | cell trafficking | innate immunity