NK cell and dendritic cell interactions in innate immune responses

Abstract

Natural killer (NK) cells are cytotoxic cells of the innate immune system. They have been found to be critical in the defense against infections and also against some tumors. Recent studies have shown that NK cells require signals from accessory cells to induce their recruitment and activation at the site of infection or tumor growth. One group of these accessory cells is the family of dendritic cells (DC). DC are antigen presenting cells, acting as sensors of the immune system with the capacity to activate the adaptive immune responses Thus, DC have been called nature s adjuvants. In the last fifteen years, another feature of DC have been under investigation, namely their interaction with NK cells, which can influence the outcome of the adaptive immune responses. In this thesis I have investigated different aspects of the interactions between NK cells and DC, including killing of DC and DC-induced activation of NK cells.

Immature resting DC are killed by activated NK cells. However, when toll like receptors (TLR) are stimulated on DC, they become functionally mature and become more resistant to NK cell mediated killing. In my first study, I investigated the role of the non-classical MHC class I molecule Qa1 in the reduced susceptibility of mature DC to NK cell lysis. We found that the interaction between Qa1 on mature DC with its inhibitory receptor NKG2A/CD94 on NK cells was crucial in protecting mature DC from NK cell-mediated killing both in vitro and in vivo, even in the absence of classical MHC class I molecules. However, mature DC were only protected from NK cells expressing NKG2A inhibitory receptor since NKG2A- NK cells lacking this molecule also displayed cytotoxicity against mature DC.

In addition to the elimination of DC by NK cells, another consequence of NK-DC interaction was investigated in this thesis, namely how TLR-stimulated DC activate NK cells. DC are no longer considered to be a homogenous cell type, instead several subtypes have been described both in mice and humans. Bone-marrow derived DC grown in GM-CSF have been mostly used in reported studies and also in paper I and III of this thesis. In paper II we explored another DC subtype, the plasmacytoid DC (pDC), that we suggest may be more potent in recruiting and activating NK cells in peripheral tissue. CpG-activated pDC injected i.p. in mice induced strong recruitment of NK cells to the peritoneal cavity, which was in part dependent on CXCR3 and CD62L. The recruited NK cells were also activated in terms of cytotoxicity against the classical NK cell target YAC-1 and were able to produce IFNgamma after restimulation ex vivo. The costimulatory molecules CD28-CD80/86 were involved in the activation of NK cells induced by stimulated pDC.

Finally, an infectious model consisting of Toxoplasma gondii (T. gondii) was used to investigate NK cells interaction with parasite-infected DC. T. gondii-infected DC were extremely sensitive to NK cell mediated lysis, which required infection with live parasites. After lysis of infected DC, parasites rapidly re-infected effector NK cells. In vivo, NK cells were found to be readily infected with T. gondii following inoculation of T. gondii-infected DC or free parasites, which was significantly reduced in mice lacking killing machinery. We speculate that NK cells kill infected DC that leads to re-infection of the NK cells and that this actually may be beneficial for the parasite to induce chronicity in its host.

In summary, this thesis provides some new insights in events that take place during NK cells interaction with DC. Hopefully, the work presented here may be beneficial in the attempts to improve therapies targeting these cells in the future.