This study investigates the role of dendritic cells (DCs) in inducing peripheral T cell unresponsiveness under steady-state conditions in vivo. The authors developed an antigen delivery system using a monoclonal antibody, DEC-205, which targets DCs in situ. This system was found to be highly efficient in inducing T cell activation and division compared to free peptide in complete Freund's adjuvant (CFA). However, the activated T cells did not produce interferon γ and the activation response was transient, with the number of antigen-specific T cells severely reduced within 7 days. Coinjection of the DC-targeted antigen and an anti-CD40 agonistic antibody led to prolonged T cell activation and immunity. The findings suggest that DCs induce transient antigen-specific T cell activation followed by deletion and unresponsiveness in the absence of additional stimuli. The study highlights the dual role of DCs in maintaining peripheral tolerance and initiating immune responses.This study investigates the role of dendritic cells (DCs) in inducing peripheral T cell unresponsiveness under steady-state conditions in vivo. The authors developed an antigen delivery system using a monoclonal antibody, DEC-205, which targets DCs in situ. This system was found to be highly efficient in inducing T cell activation and division compared to free peptide in complete Freund's adjuvant (CFA). However, the activated T cells did not produce interferon γ and the activation response was transient, with the number of antigen-specific T cells severely reduced within 7 days. Coinjection of the DC-targeted antigen and an anti-CD40 agonistic antibody led to prolonged T cell activation and immunity. The findings suggest that DCs induce transient antigen-specific T cell activation followed by deletion and unresponsiveness in the absence of additional stimuli. The study highlights the dual role of DCs in maintaining peripheral tolerance and initiating immune responses.