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,
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Departments of
*
Neurology and
Biochemistry and Molecular Biology,
Division of Pediatric Infectious Diseases,
Department of Molecular Microbiology and Immunology, and
¶ Center for Research in Occupational and Environmental Toxicology, Oregon Health and Science University, Portland, OR 97201;
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Neuroimmunology Research,
#
Neurology Service, and
**
Division of Pulmonary and Critical Care Medicine, Veterans Affairs Medical Center, Portland, OR 97201; and
Department of Molecular Neurobiology, School of Human Sciences, Waseda University, Tokorozawa, Japan
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 
1 and
1 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 
-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-
; 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.
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