CCL21 mediates CD4+ T-cell costimulation via a DOCK2/Rac-dependent pathway

Kathrin Gollmer, François Asperti-Boursin, Yoshihiko Tanaka, Klaus Okkenhaug, Bart Vanhaesebroeck, Jeffrey R. Peterson, Yoshinori Fukui, Emmanuel Donnadieu, Jens V. Stein

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43 Citations (Scopus)

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 PI3KδD910A/D910A or PI3Kγ-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 proteincoupled 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.

Original languageEnglish
Pages (from-to)580-588
Number of pages9
JournalBlood
Volume114
Issue number3
DOIs
Publication statusPublished - 2009

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Gollmer, K., Asperti-Boursin, F., Tanaka, Y., Okkenhaug, K., Vanhaesebroeck, B., Peterson, J. R., Fukui, Y., Donnadieu, E., & Stein, J. V. (2009). CCL21 mediates CD4+ T-cell costimulation via a DOCK2/Rac-dependent pathway. Blood, 114(3), 580-588. https://doi.org/10.1182/blood-2009-01-200923