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

Understanding the process of inducing T cell activation has been hampered b y the complex interactions between APC and inflammatory Th1 cells. To disso ciate Ag-specific signaling through the TCR from costimulatory signaling, r TCR ligands (RTL) containing the alpha1 and beta1 domains of HLA-DR2b (DRA* 0101:DRB1*1501) covalently linked with either the myelin basic protein pept ide 85-99 (RTL303) or CABL-b3a2 (RTL311) peptides were constructed to provi de 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 parti al activation included rapid TCR xi -chain phosphorylation, calcium mobiliz ation, and reduced extracellular signal-related kinase activity, as well as IL-10 production, but not proliferation or other obvious phenotypic change s. On restimulation with APC/peptide, the RTL-pretreated Th1 clones had red uced 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 fu rther supplemented by coactivation molecules. Activation with RTLs provides a novel strategy for generating autoantigen-specific bystander suppression useful for treatment of complex autoimmune diseases.