Dendritic cells (DCs) are key players in initiating immune responses, but they also contribute to maintaining peripheral tolerance. This study demonstrates that DCs can induce transient antigen-specific T cell activation followed by T cell deletion and unresponsiveness under steady-state conditions in vivo. Using a monoclonal antibody targeting the DC-restricted endocytic receptor DEC-205, the researchers efficiently delivered antigens to DCs, leading to T cell activation. However, these T cells did not produce IFN-γ or sustain activation, and their numbers decreased significantly within 7 days. Residual T cells became unresponsive to antigen rechallenge. When combined with an agonistic anti-CD40 antibody, the outcome shifted to prolonged T cell activation and immunity. The study concludes that in the absence of additional stimuli, DCs induce transient antigen-specific T cell activation, followed by deletion and unresponsiveness. This highlights the dual role of DCs in both initiating immune responses and maintaining peripheral tolerance. The findings suggest that DCs are critical for maintaining self-tolerance by presenting self-antigens and inducing T cell deletion or anergy. The ability to target antigens to DCs in vivo has implications for vaccine development and autoimmunity therapies.Dendritic cells (DCs) are key players in initiating immune responses, but they also contribute to maintaining peripheral tolerance. This study demonstrates that DCs can induce transient antigen-specific T cell activation followed by T cell deletion and unresponsiveness under steady-state conditions in vivo. Using a monoclonal antibody targeting the DC-restricted endocytic receptor DEC-205, the researchers efficiently delivered antigens to DCs, leading to T cell activation. However, these T cells did not produce IFN-γ or sustain activation, and their numbers decreased significantly within 7 days. Residual T cells became unresponsive to antigen rechallenge. When combined with an agonistic anti-CD40 antibody, the outcome shifted to prolonged T cell activation and immunity. The study concludes that in the absence of additional stimuli, DCs induce transient antigen-specific T cell activation, followed by deletion and unresponsiveness. This highlights the dual role of DCs in both initiating immune responses and maintaining peripheral tolerance. The findings suggest that DCs are critical for maintaining self-tolerance by presenting self-antigens and inducing T cell deletion or anergy. The ability to target antigens to DCs in vivo has implications for vaccine development and autoimmunity therapies.