Although we normally think of dendritic cells (DCs; references 1 and 2) as the “initiators” of immune responses and of their activity as confined largely to interaction with naive T cells in secondary lymphoid organs, there is emerging evidence that DCs are also important players in the effector phase of the immune response. Although rare, DCs form a dense network of cells in many tissues such as skin and respiratory and intestinal mucosa. This strategic location enables DCs to efficiently take up antigen and interact with effector CD4+ T cells in tissues to trigger cytokine secretion and activate local immune responses. Thus, we could envisage DCs in tissues as a true sentinel system with a dual mission: to alert T cells in the lymph node and trigger local defense reactions in nonlymphoid tissues. Although immature DCs, such as those in tissues, express MHC class II mainly in intracellular compartments, local inflammation causes rapid formation of MHC class II–antigen complexes and their transport to the cell membrane, and also increases expression of costimulatory molecules (3). Similarly to the situation for CD4+ T cells, DCs can become activators of effector CTLs during CD8+ T cell responses. Immature DCs, with their high phagocytic capacity, would be able to efficiently take up fragments from dying infected cells or even infectious virus and crosspresent it via MHC class I (1, 2). It is important to consider that these antigen-loaded DCs would also become easy targets of activated CTLs, which require only a handful of MHC I–antigen complexes in order to activate their cytotoxic machinery. Several recently published experiments indicate that this can indeed be the case. When allogeneic DCs, or DCs pulsed with MHC class I–binding peptides, were injected into naive or immune hosts, they were rapidly eliminated by a CD8+ T cell–dependent mechanism (4–7). In a more physiological situation, systemic infection with a DC-tropic strain of LCMV was shown to result in a dramatic depletion of DCs from the spleens of infected animals and development of severe immune suppression (8).

While the ability of DCs to act as stimulators of CD4+ effector T cells is clearly advantageous to the immune response, it is less obvious what benefits to the immune response or the host would arise from CTL-mediated killing of DCs. In all cases where DCs are not virus reservoirs, their elimination would not help clear infection but would deplete the immune system of critically important cells. On the other hand, killing of DCs by CTLs could occur at a stage when further presentation of antigen is unnecessary, or could contribute to the downregulation of the immune response to prevent excessive CTL activation. In support of this latter possibility, recent reports have implicated perforin in the regulation of CD8+ T cell clonal burst size. Perforin is a critical component of the CTL lytic granule, and its inactivation greatly blunts the cytotoxic activity of CD8+ T cells and NK cells leading to impaired viral clearance and ineffective tumor surveillance (9). In mice, perforin deficiency is also associated with enhanced accumulation of antigen-specific CD8+ T cells after viral or bacterial infection, and after DC immunization (10, 11). In humans, perforin gene defects are observed in patients with Familial Hemophagocytic Lymphohistiocytosis, a lymphoproliferative syndrome with accumulation of activated CD8+ T cells (12). There is so far no direct evidence that the enhanced accumulation of activated CD8+ T cells in perforin deficiencies is causally linked to DC elimination by CTLs, and other mechanisms remain possible. However, DC elimination in vivo has been found to be perforin dependent …