Cross-linking of 4-1BB activates TCR-signaling pathways in CD8+ T lymphocytes.
Cross-linking of 4-1BB, a member of the TNFR family, increased tyrosine phosphorylation of TCR-signaling molecules such as CD3epsilon, CD3zeta, Lck, the linker for activation of T cells, and SH2 domain-containing leukocyte phosphoprotein of 76 kDa (SLP-76). In addition, incubation of activated CD8+ T cells with p815 cells expressing 4-1BBL led to redistribution of the lipid raft domains and Lck, protein kinase C-theta;, SLP-76, and phospholipase C-gamma1 (PLC-gamma1) on the T cell membranes to the areas of contact with the p815 cells and recruitment of 4-1BB, TNFR-associated factor 2, and phospho-tyrosine proteins to the raft domains. 4-1BB ligation also caused translocation of TNFR-associated factor 2, protein kinase C-theta;, PLC-gamma1, and SLP-76 to detergent-insoluble compartments in the CD8+ T cells, and cross-linking of 4-1BB increased intracellular Ca2+ levels apparently by activating PLC-gamma1. The redistribution of lipid rafts and Lck, as well as translocation of PLC-gamma1, and degradation of IkappaB-alpha in response to 4-1BB were inhibited by disrupting the formation of lipid rafts with methyl-beta-cyclodextrin. These findings demonstrate that 4-1BB is a T cell costimulatory receptor that activates TCR-signaling pathways in CD8+ T cells.
Nam
Kyung-Ok
KO
Immunomodulation Research Center and Graduate Program in Immunology and Biomedicine, University of Ulsan, Ulsan, Korea.
Kang
Hyun
H
Shin
Su-Mi
SM
Cho
Kwang-Hyun
KH
Kwon
Byoungsuk
B
Kwon
Byoung S
BS
Kim
Sung-Jin
SJ
Lee
Hyeon-Woo
HW
D053330:4-1BB Ligand; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D015703:Antigens, CD; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002592:Cetomacrogol; D016572:Cyclosporine / Q000494:pharmacology; D003902:Detergents; D006131:Growth Inhibitors / Q000494:pharmacology; D007424:Intracellular Fluid / Q000378:metabolism; D008024:Ligands; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism; D021962:Membrane Microdomains / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D019000:Phosphotyrosine / Q000378:metabolism; D021381:Protein Transport / Q000276:immunology; D011743:Pyrimidines / Q000494:pharmacology; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism / Q000502:physiology*; D017475:Receptors, Nerve Growth Factor / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism* / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D012995:Solubility; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D047392:beta-Cyclodextrins / Q000494:pharmacology
D053330:4-1BB Ligand; C412373:AG 1879; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D003902:Detergents; D006131:Growth Inhibitors; D008024:Ligands; D011743:Pyrimidines; D011948:Receptors, Antigen, T-Cell; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; D047992:TNF Receptor-Associated Factor 2; C505715:Tnfrsf9 protein, mouse; C505975:Tnfsf9 protein, mouse; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D014409:Tumor Necrosis Factor-alpha; D047392:beta-Cyclodextrins; C108732:methyl-beta-cyclodextrin; D019000:Phosphotyrosine; D016572:Cyclosporine; D002592:Cetomacrogol; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D002118:Calcium