title: TCR ligand avidity determines the mode of B-Raf/Raf-1/ERK activation leading to the activation of human CD4+ T cell clone.
abstract: The interactions between peptide/MHC complexes and their cognate TCR are essential for various T cell responses. However, the relationship between the avidity of TCR ligand and the subsequent intracellular signaling through the TCR is still unclear. To investigate the effects of TCR ligand avidity on TCR-mediated signaling, we established L cells expressing HLA-DR4 molecules covalently linked with agonistic peptide (high-affinity ligand) or altered peptide ligand (APL; low-affinity ligand) at various densities as APC for a cognate human CD4(+) T cell clone. Using this system, we demonstrated that the T cell clone stimulated with APL/HLA-DR4 complexes presented at an excessive density provoked the up-regulation of CD69, IL-2 production and proliferation, but no detectable phosphorylation of ZAP-70/LAT/SLP-76. Furthermore, in contrast to the high-affinity stimulation, the low-affinity stimulation evoked delayed and sustained activation of the B-Raf/extracellular signal-regulated kinase (ERK) pathway without Raf-1 activation. The strength and duration of B-Raf/ERK activations closely correlated with the density of the TCR ligand. A knockdown approach confirmed that B-Raf activation was indispensable for the APL-induced T cell responses. These observations suggest that the differences in TCR-peptide/MHC interactions reflect the strength and duration of B-Raf/Raf-1/ERK activation in the human CD4(+) T cells.
authors.affiliation: Department of Immunogenetics, Graduate School of Medical Sciences,Kumamoto University, Kumamoto, Japan.
authors.forename: Hirotake
authors.initials: H
authors.lastname: Tsukamoto
authors.forename: Atsushi
authors.initials: A
authors.lastname: Irie
authors.forename: Yu-Zhen
authors.initials: YZ
authors.lastname: Chen
authors.forename: Kumiko
authors.initials: K
authors.lastname: Takeshita
authors.forename: Jeong-Ran
authors.initials: JR
authors.lastname: Kim
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Nishimura
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016645:Aotidae; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D002472:Cell Transformation, Viral; D002478:Cells, Cultured; D002999:Clone Cells; D004789:Enzyme Activation / Q000276:immunology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D015804:HLA-DR4 Antigen / Q000502:physiology; D006567:Herpesvirus 2, Saimiriine; D006801:Humans; D019169:Jurkat Cells; D007739:L Cells; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D016716:PC12 Cells; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism*; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism*; D051381:Rats; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*
chemical_list: D015804:HLA-DR4 Antigen; D008024:Ligands; D011948:Receptors, Antigen, T-Cell; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf; D048049:Extracellular Signal-Regulated MAP Kinases