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Gollmer K , Asperti-Boursin F , Tanaka Y , Okkenhaug K , Vanhaesebroeck B , Peterson JR , Fukui Y , Donnadieu E , Stein JV
CCL21 mediates CD4(+) T-cell costimulation via a DOCK2/Rac-dependent pathway
Blood. 2009 Jul;114(3) :580-588
PMID: 19451552    PMCID: PMC2713469    URL: https://www.ncbi.nlm.nih.gov/pubmed/19451552
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Abstract
CD4(+) T cells use the chemokine receptor CCR7 to home to and migrate within lymphoid tissue, where T-cell activation takes place. Using primary T-cell receptor (TCR)-transgenic (tg) CD4(+) T cells, we explored the effect of CCR7 ligands, in particular CCL21, on T-cell activation. We found that the presence of CCL21 during early time points strongly increased in vitro T-cell proliferation after TCR stimulation, correlating with increased expression of early activation markers. CCL21 costimulation resulted in increased Ras- and Rac-GTP formation and enhanced phosphorylation of Akt, MEK, and ERK but not p38 or JNK. Kinase-dead Pl3K delta(D910A/D910A) or Pl3K gamma-deficient TCR-tg CD4(+) T cells showed similar responsiveness to CCL21 costimulation as control CD4(+) T cells. Conversely, deficiency in the Rac guanine exchange factor DOCK2 significantly impaired CCL21-mediated costimulation in TCR-tg CD4(+) T cells, concomitant with impaired Rac- but not Ras-GTP formation. Using lymph node slices for live monitoring of T-cell behavior and activation, we found that G protein-coupled receptor signaling was required for early CD69 expression but not for Ca2(+) signaling. Our data suggest that the presence of CCL21 during early TCR signaling lowers the activation threshold through Ras- and Rac-dependent pathways leading to increased ERK phosphorylation. (Blood. 2009; 114: 580-588)
Notes
ISI Document Delivery No.: 471ML Gollmer, Kathrin Asperti-Boursin, Francois Tanaka, Yoshihiko Okkenhaug, Klaus Vanhaesebroeck, Bart Peterson, Jeffrey R. Fukui, Yoshinori Donnadieu, Emmanuel Stein, Jens V. AMER SOC HEMATOLOGY