Journal
BLOOD
Volume 114, Issue 3, Pages 580-588Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2009-01-200923
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Funding
- Swiss National Foundation [SNF3100A0-107510]
- EU-MEXT [25405]
- Department of Defense Research Program [W81XWH-05-1-0200]
- National Institutes of Health [GM083025]
- BBSRC [BBS/E/B/0000C236] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BBS/E/B/0000C236] Funding Source: researchfish
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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)
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