AILIM/ICOS-mediated elongation of activated T cells is regulated by both the PI3-kinase/Akt and Rho family cascade.
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.
Nukada
Yuko
Y
Department of Biological Science and Technology, Faculty of Industrial Science and Technology, Tokyo University of Science, Yamazaki 2641, Noda, Chiba 278-8510, Japan.
Okamoto
Naokazu
N
Konakahara
Shu
S
Tezuka
Katsunari
K
Ohashi
Kazumasa
K
Mizuno
Kensaku
K
Tsuji
Takashi
T
D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism*; D016764:Cell Polarity; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D006801:Humans; D060889:Inducible T-Cell Co-Stimulator Protein; D008213:Lymphocyte Activation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000502:physiology; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D000945:Antigens, Differentiation, T-Lymphocyte; C556692:ICOS protein, human; D060889:Inducible T-Cell Co-Stimulator Protein; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020741:rho GTP-Binding Proteins