The lifespan and survival of dendritic cells (DC) in vivo are potentially critical to the expansion of T cell immune responses. We have previously reported that DC loaded with specific antigen are rapidly eliminated by cytotoxic T lymphocytes (CTL) in vivo, but the site, mechanism, and consequences of DC elimination were not defined. In this article we show that DC elimination in vivo occurs in a perforin-dependent manner and does not require IFN-␥ or the presence of CD4 ؉ CD25 ؉ regulatory T cells. Most importantly, failure to eliminate DC had profound consequences on the CTL immune response. Perforin-deficient mice showed a progressive increase in the numbers of antigen-specific CD8 ؉ T cells after repeated immunizations with DC. In contrast, in control mice the number of antigen-specific CD8 ؉ T cells did not notably increase with repeated immunizations. Lastly, we also show that CTLmediated elimination of DC occurs in peripheral tissues but not in the lymph node. Our data suggest that CTL act as ''gatekeepers'' that control access of antigen-loaded DC into the lymph node, thereby preventing continued expansion of antigen-specific T cells.cytotoxic T cells ͉ immunoregulation ͉ killing D endritic cells (DC) are powerful antigen-presenting cells that are critical for the initiation of CD4 ϩ and CD8 ϩ T cell responses. DC reside in peripheral tissues where they take up antigens from the external environment, then migrate to the lymph nodes where they interact with antigen-specific T cells and induce their activation to proliferation and effector function (1, 2). The lifespan of DC once in the lymph node is thought to be relatively brief, but experimental estimates have not yielded a consistent figure (3-5).The mechanism and regulation of DC survival and death (6, 7) are likely to be important in maintaining the homeostatic balance of the immune system. A few reports have linked extended survival of DC to enhanced or dysregulated T cell immune responses and lymphoproliferative disease (8-10). In contrast, reduced survival of DC has been associated with impaired immune responses (7). It is presently unclear whether T cells also influence the lifespan of DC in an antigen-specific fashion. In lymph nodes of mice adoptively transferred with CD4 ϩ T cell receptor (TCR) transgenic T cells, DC presenting specific antigen disappear more rapidly than DC not presenting antigen (11), suggesting that T cells may have a role in regulating DC numbers and survival. Experiments using infection with Listeria or malaria also suggest that the number of antigen-presenting cells becomes limiting during the early phases of CD8 ϩ immune responses and prevents the continued expansion of antigen-specific T cells (12, 13). Together, these experiments suggest the attractive hypothesis that T cells may be able to regulate their own responses in a feedback fashion, by affecting the survival of antigen-presenting DC.We have previously reported that DC loaded with antigen and injected s.c. into immune mice are rapidly eliminated by CD8 ϩ T cel...