Phospholipase Cβ is critical for T cell chemotaxis

Chemokines acting through G protein-coupled receptors play an essential role in the immune response. PI3K and phospholipase C (PLC) are distinct signaling molecules that have been proposed in the regulation of chemokine-mediated cell migration. Studies with knockout mice have demonstrated a critical role for PI3K in G(alpha i) protein-coupled receptor-mediated neutrophil and lymphocyte chemotaxis. Although PLC beta is not essential for the chemotactic response of neutrophils, its role in lymphocyte migration has not been clearly defined. We compared the chemotactic response of peripheral T cells derived from wild-type mice with mice containing loss-of-function mutations in both of the two predominant lymphocyte PLC beta isoforms (PLC beta 2 and PLC beta 3), and demonstrate that loss of PLC beta 2 and PLC beta 3 significantly impaired T cell migration. Because second messengers generated by PLC beta lead to a rise in intracellular calcium and activation of PKC, we analyzed which of these responses was critical for the PLC beta-mediated chemotaxis. Intracellular calcium chelation decreased the chemotactic response of wild-type lymphocytes, but pharmacologic inhibition of several PKC isoforms had no effect.. Furthermore, calcium efflux induced by stromal cell-derived factor-l alpha was undetectable in PLC beta 2 beta-null lymphocytes, suggesting that the migration defect is due to the impaired ability to increase intracellular calcium. This study demonstrates that, in contrast to neutrophils, phospholipid second messengers generated by PLC beta play a critical role in T lymphocyte chemotaxis.