Antigen presenting cells (APCs) initiate CD4+ T cell-mediated immune responses via the presentation of protein antigens on MHC class II (MHCII) molecules. Numerous APCs are capable of activating naïve T cells in vitro , however, the required APCs for effective CD4+ T cell-dependent immunity in vivo are unknown. We analyzed the APC requirements for CD4+ T cell priming by employing transgenic mice and/or bone marrow chimeras that have restricted MHCII expression to distinct cellular compartments. We demonstrate that antigen processing and presentation by both lymphoid-resident and migratory tissue DCs is required for efficient clonal selection and expansion of CD4+ T cells following subcutaneous immunization. Surprisingly, the tissue-derived DCs migrating from the site of the immunization cannot alone initiate naïve T cell priming. Early antigen presentation by lymphoid-resident DCs activates and traps antigen-specific T cells in the draining LN, without sufficing for clonal expansion. Migratory DCs then interact with the CD4+ T cells retained in the LN to induce proliferation. Therefore, distinct DC subsets cooperate to alert and trap the appropriate cell and then license its expansion and differentiation. Despite defective early T cell priming in the absence of migratory DC antigen presentation, we found lymphoid-resident DCs still promote long-term control of Leishmania major parasites after intradermal low dose infection. The minimally sufficient APC for priming naïve CD4+ T cells is the lymphoid-resident DC. The cooperation of both lymphoid-resident and migratory DC antigen presentation vastly enhances the efficiency of T cell priming.
