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,
Departments of
*
Neurology,
Biochemistry and Molecular Biology, and
Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, OR 97239; and
Department of Neuroimmunology Research, Veterans Affairs Medical Center, Portland, OR 97207
Recombinant TCR ligands (RTLs) consisting of covalently linked 
1 and 
1 domains of MHC class II molecules tethered to specific antigenic peptides represent minimal TCR ligands. In a previous study we reported that the rat RTL201 construct, containing RT1.B MHC class II domains covalently coupled to the encephalitogenic guinea pig myelin basic protein (Gp-MBP72–89) peptide, could prevent and treat actively and passively induced experimental autoimmune encephalomyelitis in vivo by selectively inhibiting Gp-MBP72–89 peptide-specific CD4+ T cells. To evaluate the inhibitory signaling pathway, we tested the effects of immobilized RTL201 on T cell activation of the Gp-MBP72–89-specific A1 T cell hybridoma. Activation was exquisitely Ag-specific and could not be induced by RTL200 containing the rat MBP72–89 peptide that differed by a threonine for serine substitution at position 80. Partial activation by RTL201 included a CD3
p23/p21 ratio shift, ZAP-70 phosphorylation, calcium mobilization, NFAT activation, and transient IL-2 production. In comparison, anti-CD3
treatment produced stronger activation of these cellular events with additional activation of NF-
B and extracellular signal-regulated kinases as well as long term increased IL-2 production. These results demonstrate that RTLs can bind directly to the TCR and modify T cell behavior through a partial activation mechanism, triggering specific downstream signaling events that deplete intracellular calcium stores without fully activating T cells. The resulting Ag-specific activation of the transcription factor NFAT uncoupled from the activation of NF-B or extracellular signal-regulated kinases constitutes a unique downstream activation pattern that accounts for the inhibitory effects of RTL on encephalitogenic CD4+ T cells.
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