It is generally accepted that priming of antitumor CD8 ؉ cytotoxic T lymphocytes (CTLs) needs help that can be provided by CD4 ؉ T cells. We show that interactions between dendritic cells (DCs) and natural killer (NK) cells can bypass the T helper arm in CTL induction. Bone marrow-derived DCs caused rejection of the A20 lymphoma and induced tumor-specific long-term memory, although they were not loaded with tumor-derived antigen. Experiments using CD40 ؊ knock-out mice and cell depletion showed that this effect did not require CD4 ؉ cells. Both primary rejection and long-term CTL memory were the result of NK cell activation by DCs. NK cytotoxicity, which was necessary for primary rejection, was dependent on expression of natural killer group 2 D (NKG2D) ligands on tumor cells. Blocking of these ligands using NKG2D tetramers abrogated tumor killing in vitro and in vivo. The long-term response was due to CTLs directed against antigen(s) expressed on A20 and in vitrodifferentiated DCs. The mechanism leading to CD4 ؉ helper cell-independent CTL responses was elucidated as a cascade that was initiated by NK cell activation. This pathway was dependent on interferon-␥ expression and involved priming endogenous DCs for interleukin-12 production. Our data suggest a novel pathway linking innate and adaptive immunity. ( IntroductionInduction of efficient immune responses requires a coordinated interplay between innate and adaptive immune effector systems. Dendritic cells (DCs) are components of the innate immune system that activate specific effectors of adaptive immunity. 1,2 In an immature state, DCs are able to ingest antigen (Ag). Following a maturation process that involves migration to lymphoid tissues, down-regulation of Ag uptake and upregulation of major histocompatibility complex (MHC) and costimulatory molecules, DCs present antigenic peptides to T lymphocytes. 1 Exogenous proteins are taken up and processed by DCs and presented to CD4 ϩ cells in association with MHC class II molecules, whereas intracellular Ags are presented by MHC class I molecules to CD8 ϩ cytotoxic T lymphocytes (CTLs). There is, however, emerging evidence that exogenous proteins can also be directed to the endogenous presentation pathway, thus leading to CTL induction, a process referred to as cross-presentation. Efficient generation of CTLs from naive CD8 ϩ T cells needs help from CD4 ϩ T cells. [3][4][5] This help involves secretion of cytokines and CD40/CD40L interactions that lead to increased expression of costimulatory molecules on DCs and to induction of interleukin-12 (IL-12). 6 As shown in mouse models, CD4 ϩ T cells are pivotal for protection against tumors and can even mediate tumor rejection independently of CD8 ϩ T lymphocytes, if they are biased toward a T helper 1 (Th1) response. 7 Expression of CD40 by DCs is crucial for the production of Th1 cytokines such as IL-12 and for tumor protection. 7,8 Natural killer (NK) cells are effector cells of the innate immune system that exert direct cytotoxic functions. 9 These are determ...

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