T-cell activation in the absence of co-stimulatory signals can lead to induction of anergy. Professional antigen-presenting cells (APCs) of bone marrow origin, such as macrophages and dendritic cells, can provide co-stimulation through molecules such as B7-1 and B7-2. In addition, cells of epithelial origin can function as 'non-professional' APCs when activated. In these circumstances, the functional consequences of the T cell-APC interaction may differ, perhaps due to the nature of the co-stimulatory pathways utilized and/or the cytokines encountered by the T cell. Here, Brian Nickoloff and Laurence Turka suggest that these differences may be important in regulating immune responses to local antigens and also in maintaining self-tolerance.