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Is Critical for T Cell Chemotaxis1
* Department of Medicine,
Department of Pharmacology,
Department of Pathology and Laboratory Medicine, Abramson Family Cancer Research Institute,
Department of Biology, University of Pennsylvania, and
¶ Department of Pediatrics, Division of Pathology, Children’s Hospital of Philadelphia, Philadelphia, PA 19104; and
|| Department of Genetics and Developmental Biology, University of Connecticut Health Center, Farmington, CT 06030
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
i protein-coupled receptor-mediated neutrophil and lymphocyte chemotaxis. Although PLC
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 isoforms (PLC2 and PLC3), and demonstrate that loss of PLC2 and PLC3 significantly impaired T cell migration. Because second messengers generated by PLC lead to a rise in intracellular calcium and activation of PKC, we analyzed which of these responses was critical for the PLC-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-1 was undetectable in PLC23-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 play a critical role in T lymphocyte chemotaxis.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by funds from the National Institutes of Health.
2 Address correspondence and reprint requests to Dr. Charles S. Abrams, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104. E-mail address: abrams{at}mail.med.upenn.edu
3 Abbreviations used in this paper: SDF-1, stromal cell-derived factor-1; PLC, phospholipase C; PIP2, phosphatidylinositol 4,5-bisphosphate; IP3, inositol 1,4,5-trisphosphate; DAG, diacylglycerol; WT, wild type.
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