Protein kinase C-δ and -β coordinate flow-induced directionality and deformation of migratory human blood T-lymphocytes

T-tym phocyte migration under flow is critical for immune responses, but the mechanisms by which flow modulates the migratory beha- viors of T-lymphocytes remain unclear. Human peripheral blood T-lymphocytes （PBTLs）, when stimulated with phorboL 12-myristate 13-acetate （PMA）, stretched their ceU bodies dramatically and moved alongthe flow direction. In contrast, stromal ceil-derived factor- lα-stimulated PBTI.s deformed and migrated in a random manner. Here we elucidated the molecular mechanisms underlying flow- induced directionality and deformation of PMA-stimulated PBTLs. PMA primed PBTLs for polarization under flow, with protein kinase C （PKC）-δ enriched in the leading edge, PKC-β1 in the microtubuie organizing center, and PKC-1311 in the uropod and peripheral region. PKC-δ regulated cell protrusions in the leading edge through Tiaml/Racl/caLmoduUn, whereas PKC-β regulated RhoA/Rho- associated kinase activity and microtubule stability to modulate uropod contractility and detachment. Our findings indicate that PKC-δ and -β coordinate in the cell Leading edge and uropod, respectively, to modu｜ate the directionality and deformability of migratory T-Lymphocytes under flow.