Dendritic cells (DCs) are specialized antigen-presenting cells (APCs) that have a dominant role in initiating T-cell responses. The skin is populated by at least two subsets of DCs: Langerhans cells (LCs), which form a contiguous network throughout the epidermis, and dermal DC. According to the conventional paradigm, LCs perform a sentinel function by detecting skin pathogens and integrating this information to T cells in the lymph nodes (LNs). However, recent data have highlighted only the importance of dermal DC in skin immunity, while the role of LCs remains an enigma. The arrival of skin DCs to the LNs and activation of CD8+ T cells are thought to take place within 24 hrs after exposure to an antigen. We have recently described that following intradermal immunization with plasmid DNA, CD8+ T cell priming initiates 4 days post-immunization and reaches its maximal level on day 15. We also showed that arrival of APCs from the skin occurs 3 days after the immunization and proceeds for almost two weeks. Such pattern of migration is consistent with the reported migration kinetics of LCs but not of dermal DCs that enter the LN within the first 24 hrs post-immunization. We recently generated unpublished data demonstrating that T-cell priming correlates with the late arrival of CD11c+DEC205med cells (LCs) and not with that of CD11c+DEC205hi cells (dermal DCs) that are first to enter the LNs. This has led us to the hypothesis that LCs might play an important role in T-cell priming during intradermal DNA immunization. Using cellular immunology approaches and langerin-DTR and CD11c-DTR transgenic mice, we will address this issue by performing experiments falling under three specific aims. (i) Characterizing the type of skin DCs involve in antigen presentation. (ii) Identifying the factors leading to the slow-rate antigen presenting activity. (iii) Assessing the quality of the elicited immunity. These complementary aims should reveal a novel role for LCs in T-cell priming.