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

T-lymphocyte migration under flow is critical for immune responses, but the mechanisms by which flow modulates the migratory behaviors of T-lymphocytes remain unclear. Human peripheral blood T-lymphocytes (PBTLs), when stimulated with phorbol 12-myristate 13-acetate (PMA), stretched their cell bodies dramatically and moved along the flow direction. In contrast, stromal cell-derived factor-1 alpha-stimulated PBTLs 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)-delta enriched in the leading edge, PKC-beta I in the microtubule organizing center, and PKC-beta II in the uropod and peripheral region. PKC-delta regulated cell protrusions in the leading edge through Tiam1/Rac1/calmodulin, whereas PKC-beta regulated RhoA/Rho-associated kinase activity and microtubule stability to modulate uropod contractility and detachment. Our findings indicate that PKC-delta and -beta coordinate in the cell leading edge and uropod, respectively, to modulate the directionality and deformability of migratory T-lymphocytes under flow.