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Blood, 13 August 2009, Vol. 114, No. 7, pp. 1366-1373.
Prepublished online as a Blood First Edition Paper on June 11, 2009; DOI 10.1182/blood-2008-08-175869.


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IMMUNOBIOLOGY

Activation of Wnt5A signaling is required for CXC chemokine ligand 12–mediated T-cell migration

Manik C. Ghosh1, Gary D. Collins1, Bolormaa Vandanmagsar1, Kalpesh Patel1, Margaret Brill1, Arnell Carter1, Ana Lustig1, Kevin G. Becker2, William W. Wood, III2, Chineye D. Emeche1, Amanda D. French1, Michael P. O'Connell1, Mai Xu1, Ashani T. Weeraratna1, and Dennis D. Taub1

1 Laboratory of Immunology and 2 Research Resources Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD

Chemokines mediate the signaling and migration of T cells, but little is known about the transcriptional events involved therein. Microarray analysis of CXC chemokine ligand (CXCL) 12–treated T cells revealed that Wnt ligands are significantly up-regulated during CXCL12 treatment. Real-time polymerase chain reaction and Western blot analysis confirmed that the expression of noncanonical Wnt pathway members (eg, Wnt5A) was specifically up-regulated during CXCL12 stimulation, whereas β-catenin and canonical Wnt family members were selectively down-regulated. Wnt5A augmented signaling through the CXCL12-CXCR4 axis via the activation of protein kinase C. Moreover, Wnt5A expression was required for CXCL12–mediated T-cell migration, and rWnt5A sensitized human T cells to CXCL12-induced migration. Furthermore, Wnt5A expression was also required for the sustained expression of CXCR4. These results were further supported in vivo using EL4 thymoma metastasis as a model of T-cell migration. Together, these data demonstrate that Wnt5A is a critical mediator of CXCL12-CXCR4 signaling and migration in human and murine T cells.


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