Natural Killer Cells Activated by MHC Class ILow Targets Prime Dendritic Cells to Induce Protective CD8 T Cell Responses

Abstract

Conserved molecular patterns derived from pathogenic microorganisms prime antigen-presenting dendritic cells (DC) to induce adaptive T cell responses. In contrast, virus-infected or tumor cells that express low levels of major histocompatibility complex (MHC) class I activate natural killer (NK) cells for direct killing. It is unknown whether NK cell recognition of MHC class I(low) targets can also induce adaptive T cell responses. Here, we show that MHC class I(low) targets initiate a cascade of immune responses, starting with the immediate activation of NK cells. The activated NK cells then prime DC to produce IL-12 and to induce highly protective CD8 T cell memory responses. Therefore, sensing of MHC class I(low) targets by NK cells can link innate and adaptive immunity to induce protective T cell responses and may alarm the immune system during early infection with noncytopathic viruses.

Requirements for control of B‐cell lymphoma by NK cells

“…This was also suggested by our previous studies where we showed that in normal mice, transplanted MHC class I-positive lymphomas are effectively controlled provided (i) NK cells are previously activated in vivo by injecting DC or CpG-ODN and (ii) sufficient amounts of NKG2D-L are expressed by the tumor [22]. Transplanted MHC class I low lymphomas with sufficient NKG2D-L levels are rejected even without preceding NK-cell activation [6]. Whereas the priming signal provides unspecific activation, the tumor specificity of the NK-cell response may be mediated by the second signal.…”

“…In transplantation models, injection of tumor cells with NK cell-activating potential gave rise to NK-cell cytotoxicity and IFN-g expression and, eventually, to CTL responses [6,43]. Since this effect was dependent on injection of sufficiently high cell numbers [6], we anticipated that such tumor transplantation models rather reflect the situation encountered in viral infections where rapid inhibition of MHC class I expression in large numbers of infected cells leads to NK-cell activation.…”

“…Since this effect was dependent on injection of sufficiently high cell numbers [6], we anticipated that such tumor transplantation models rather reflect the situation encountered in viral infections where rapid inhibition of MHC class I expression in large numbers of infected cells leads to NK-cell activation. The present work presents evidence that a progressively growing, endogenous tumor indeed fails to activate NK-cell effector functions.…”

“…We were therefore interested in the mechanisms of NK-cell activation in tumor surveillance in vivo and we specifically investigated the role of ''missing self'' and of NKG2D/ligand interactions as well as the mechanisms underlying tumor escape. We previously showed that missing self can induce strong and protective NK-cell responses in a tumor transplantation model [6], but this may not reflect the situation in endogenous tumors. Therefore, we used a c-myc transgenic model of spontaneously arising lymphoma [29] and analyzed lack of inhibiting and presence of NKG2D-mediated activating signals in the light of the two-step NK-cell activation hypothesis.…”

“…Inhibitory receptors interacting with MHC selfmolecules interfere with positive signaling, thus protecting normal tissue from NK-cell attack. As predicted by the ''missing self hypothesis'', interaction of NK cells with target cells expressing reduced levels of self MHC, such as virus-infected or tumor cells, ignites the lytic machinery [3][4][5][6]. Inhibitory receptors of mouse NK cells comprise several Ly49 receptors, CD94/NKG2A [7] or CD48 [8].…”