Activation of Wnt5A signaling is required for CXC chemokine ligand 12-mediated T-cell migration.
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 beta-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.
Ghosh
Manik C
MC
Laboratory of Immunology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
Collins
Gary D
GD
Vandanmagsar
Bolormaa
B
Patel
Kalpesh
K
Brill
Margaret
M
Carter
Arnell
A
Lustig
Ana
A
Becker
Kevin G
KG
Wood
William W
WW
Emeche
Chineye D
CD
French
Amanda D
AD
O'Connell
Michael P
MP
Xu
Mai
M
Weeraratna
Ashani T
AT
Taub
Dennis D
DD
D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics / Q000276:immunology*; D054377:Chemokine CXCL12 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D051153:Wnt Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000071818:Wnt-5a Protein; D051176:beta Catenin / Q000235:genetics / Q000276:immunology
C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D011518:Proto-Oncogene Proteins; D019718:Receptors, CXCR4; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C438615:Wnt5a protein, mouse; D051176:beta Catenin