A new T-cell activation mode for suboptimal doses of antigen under the full activation of Tcells with different specificity

Loss of tolerance for autoantigens is a common feature in autoimmune diseases. Bystander T-cell activation is the activation of Tcells to produce functional changes through TCR-independent stimulation. Although bystander activation may be related to tolerance loss to multiple autoantigens, the activation mechanism of Tcells directed to an autoantigen with limited amount is not clear. We investigated an activation mode of Tcells (designated as associator Tcells) directed to a suboptimal dose of cognate antigen X in the presence of fully activated Tcells (designated as responder Tcells) directed to an optimal dose of antigen Y. In in vitro coculture, the activation of associator Tcells was dependent on the presentation of antigen X, and soluble factors from activated responder Tcells were not sufficient. Therefore, we conclude this activation mode is different from bystander activation and named it extended antigen priming (EAP). Tcells with EAP showed a different phenotype compared to conventionally primed cells, suggesting the unique nature of EAP. Intriguingly, EAP was dependent on the CD40-CD40L signaling pathway. Thus, the EAP model is a T-cell activation mode for suboptimal dose of antigen and presumably related to the immune response to autoantigens in autoimmune status.