Rudimentary TCR signaling triggers default IL-10 secretion by human Th1 cells

被引:48
作者
Burrows, GG
Chou, YK
Wang, CH
Chang, JW
Finn, TP
Culbertson, NE
Kim, J
Bourdette, DN
Lewinsohn, DA
Lewinsohn, DM
Ikeda, M
Yoshioka, T
Allen, CN
Offner, H
Vandenbark, AA
机构
[1] Oregon Hlth Sci Univ, Dept Neurol, Portland, OR 97201 USA
[2] Oregon Hlth Sci Univ, Dept Biochem & Mol Biol, Portland, OR 97201 USA
[3] Oregon Hlth Sci Univ, Div Pedit Infect Dis, Portland, OR 97201 USA
[4] Oregon Hlth Sci Univ, Dept Mol Microbiol & Immunol, Portland, OR 97201 USA
[5] Oregon Hlth Sci Univ, Ctr Res Occupat & Environm Toxicol, Portland, OR 97201 USA
[6] Vet Affairs Med Ctr, Neurol Serv, Portland, OR 97201 USA
[7] Vet Affairs Med Ctr, Div Pulm & Crit Care Med, Portland, OR 97201 USA
[8] Waseda Univ, Sch Human Sci, Dept Mol Neurobiol, Tokorozawa, Saitama, Japan
关键词
D O I
10.4049/jimmunol.167.8.4386
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Understanding the process of inducing T cell activation has been hampered by the complex interactions between APC and inflammatory Th1 cells. To dissociate Ag-specific signaling through the TCR from costimulatory signaling, rTCR ligands (RTL) containing the alpha1 and beta1 domains of HLA-DR2b (DRA*0101:DRB1*1501) covalently linked with either the myelin basic protein peptide 85-99 (RTL303) or CABL-b3a2 (RTL311) peptides were constructed to provide a minimal ligand for peptide-specific TCRs. When incubated with peptide-specific Th1 cell clones in the absence of APC or costimulatory molecules, only the cognate RTL induced partial activation through the TCR. This partial activation included rapid TCR xi -chain phosphorylation, calcium mobilization, and reduced extracellular signal-related kinase activity, as well as IL-10 production, but not proliferation or other obvious phenotypic changes. On restimulation with APC/peptide, the RTL-pretreated Th1 clones had reduced proliferation and secreted less IFN-gamma; IL-10 production persisted. These findings reveal for the first time the rudimentary signaling pattern delivered by initial engagement of the external TCR interface, which is further supplemented by coactivation molecules. Activation with RTLs provides a novel strategy for generating autoantigen-specific bystander suppression useful for treatment of complex autoimmune diseases.
引用
收藏
页码:4386 / 4395
页数:10
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