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International Immunology Advance Access originally published online on October 31, 2006
International Immunology 2006 18(12):1815-1824; doi:10.1093/intimm/dxl115
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© The Japanese Society for Immunology. 2006. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

AILIM/ICOS-mediated elongation of activated T cells is regulated by both the PI3-kinase/Akt and Rho family cascade

Yuko Nukada1,2, Naokazu Okamoto1,2, Shu Konakahara1,2, Katsunari Tezuka3, Kazumasa Ohashi4, Kensaku Mizuno4 and Takashi Tsuji1,2

1 Department of Biological Science and Technology, Faculty of Industrial Science and Technology, Tokyo University of Science, Yamazaki 2641, Noda, Chiba 278-8510, Japan
2 Tissue Engineering Research Center, Research Institute of Biological Science, Tokyo University of Science, Yamazaki 2641, Noda, Chiba 278-8510, Japan
3 Pharmaceutical Research Laboratory, JT Inc., Takatsuki, Osaka 569-1125, Japan
4 Department of Biomolecular Sciences, Graduate School of Life Sciences, Tohoku University, Miyagi 980-8578, Japan

Correspondence to: T. Tsuji; E-mail: t-tsuji{at}rs.noda.tus.ac.jp

T-cell migration and movement is a critical component of a fully functional immune system. Activation-inducible lymphocyte immunomediatory molecule/inducible co-stimulator (AILIM/ICOS), which is a member of CD28 co-stimulatory receptor family, induces both activated T-cell migration underneath tumor necrosis factor {alpha}-treated human umbilical vein endothelial cell layers and also the morphological polarization of activated T cells. In our current study, we have investigated the signaling mechanisms underlying the morphological polarization of activated T cells, initiated by AILIM/ICOS signaling. AILIM/ICOS signaling induces the activation of phosphoinositide-3 (PI3)-kinase, the product of which, phosphatidylinositol 3,4,5-trisphosphate (PIP3), was found to be localized in the lamellipodia at the front part of the cells. Phosphorylated Akt is also co-localized with PIP3 and filamentous actin in lamellipodia and the PI3-kinase/Akt signaling cascade has critical roles in T-cell polarization and lamellipodia formation via the re-organization of the actin cytoskeleton. Rho family members and their downstream effectors, Rho-associated kinase and p21-activated kinase (PAK), are also involved in AILIM/ICOS-mediated elongation. The PAK family members are serine/threonine kinase downstream effectors of both Rac and Cdc42. PAK3 is induced by the activation of T cells, whereas PAK1 is constitutively expressed in both naive and activated T cells. During the elongation, not only PAK1 but also PAK3 play an essential role through the phosphorylation of their conservative autophosphorylation sites and catalytic domain. Ser-244 phosphorylation, which is a putative Akt phosphorylation site, on PAK3 but not on PAK1 also regulates the morphological polarization of activated T cells by AILIM/ICOS signaling. Both the PI3-kinase/Akt and Rho family cascades operate coordinately to induce the forward migration of activated T cells by AILIM/ICOS signaling.

Keywords: cell elongation, cell polarization, co-stimulatory molecule

Transmitting editor: K. Sugamura


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