Recombinant TCR ligand induces early TCR signaling and a unique pattern of downstream activation

Chunhe Wang, Jeffery L. Mooney, Roberto Meza-Romero, Yuan K. Chou, Jianya Huan, Arthur A. Vandenbark, Halina Offner, Gregory G. Burrows

Research output: Contribution to journalArticle

43 Scopus citations

Abstract

Recombinant TCR ligands (RTLs) consisting of covalently linked α 1, and β1, 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-MBP 72-89-specific A1 T cell hybridoma. Activation was exquisitely Ag-specific and could not be induced by RTL200 containing the rat MBP 72-89 peptide that differed by a threonine for serine substitution at position 80. Partial activation by RTL201 included a CD3ζ p23/p21 ratio shift, ZAP-70 phosphorylation, calcium mobilization, NFAT activation, and transient IL-2 production. In comparison, anti-CD3ε treatment produced stronger activation of these cellular events with additional activation of NF-κB 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-κB or extracellular signal-regulated kinases constitutes a unique downstream activation pattern that accounts for the inhibitory effects of RTL on encephalitogenic CD4+ T cells.

Original languageEnglish (US)
Pages (from-to)1934-1940
Number of pages7
JournalJournal of Immunology
Volume171
Issue number4
DOIs
StatePublished - Aug 15 2003

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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