Different "professional" antigen-presenting cells (APC) have unique characteristics that favor or restrict presentation of microbial antigens to T cells, depending on the organism. Cryptococcus neoformans is a pathogenic yeast that presents unique challenges to APC, including its large size, its rigid cell wall, and its ability to stimulate T cells as a mitogen. T-cell proliferation in response to the C. neoformans mitogen (CnM) requires phagocytosis and processing of the organisms by accessory cells prior to presentation of CnM to T cells. Because of the requirement for uptake of the organism and more limited costimulatory requirements of mitogens, macrophages might be the most likely cellular source for the accessory cell. However, the present study demonstrates that a transiently adherent cell that was CD3(-), CD14(-), CD19(-), CD56(-), HLA-DR(+), and CD83(+) with a dendritic morphology, rather than monocyte-derived or tissue (alveolar) macrophages, was the most efficient APC for presentation of CnM. A large number of these cells bound and internalized the organism, and only a small number of dendritic cells were required for presentation of the mitogen to T cells. Further, the mannose receptor and Fcgamma receptor II were required for presentation of C. neoformans, as blocking either of these receptors abrogated both uptake of C. neoformans and lymphocyte proliferation in response to CnM. These studies demonstrate the surprising fact that dendritic cells are the most efficient accessory cells for CnM.