NKG2D is a key receptor for the activation of immune effector cells, mainly Natural Killer cells and T lymphocytes, in infection, cancer and autoimmune diseases. Since the detection of ligands for NKG2D in sera of cancer patients is, in many human models, indicative of prognosis, a large number of studies have been undertaken to improve understanding of the biology regulating this receptor and its ligands, with the aim of translating this knowledge into clinical practice. Although it is becoming clear that the NKG2D system can be used as a tool for diagnosis and manipulated for therapy, some questions remain open due to the complexity associated with the existence of a large number of ligands, each one of them displaying distinct biological properties. In this review, we have highlighted some key aspects of this system that differ between humans and mice, including the properties of NKG2D, as well as the genetic and biochemical complexity of NKG2D-ligands. All of these features affect the characteristics of the immune response exerted by NKG2D-expressing cells and are likely to be important factors in the clearance of a tumour or the development of autoimmunity. Implementation of more global analyses, including information on genotype, transcription and protein properties (cellular vs released to the blood stream) of NKG2D-ligands expressed in patients will be necessary to fully understand the links between this system and disease progression.

In recent studies, we showed that murine fetal liver cells from progeny exposed to benzo(alpha)pyrene in utero by intraperitoneal injection of the dam at midpregnancy (12 d) suppressed cell proliferation in an allogeneic mixed lymphocyte response. On the other hand, fetal liver cells from the corn oil (vehicle for the carcinogen)-exposed progeny (control) appeared to enhance proliferation. Suppression or enhancement appeared to be mediated by fetal liver bearing CD8+ and Lyt 1+ (CD5+) cells. Despite these manifestations, the role of third-party cells needs to be considered. As a first premise, adherent cells were targeted as possible third-party cells. To test the role of the adherent cells, liver cells from benzo(alpha)pyrene-exposed fetuses were treated with ficoll-hypaque, and the interface cells were fractionated through glass wool or nylon wool. It is known that adhering cells, macrophages and B cells, readily attach to glass or nylon wool. The effluent cells and the adherent cells were cultured with syngeneic responder cells and allogeneic stimulator cells in a mixed lymphocyte response. The results showed that benzo(alpha)pyrene-effluent cells led to the enhancement of proliferation in the mixed lymphocyte response, while benzo(alpha)pyrene-adherent cells led to suppression. The effluent and adherent cells of corn oil controls did not modify cell proliferation in the mixed lymphocyte response. These data suggest that a third-party cell, reasonably the macrophage or possibly B cells or both, since these are adherent cells, play a decided role in mediating suppression in the benzo(alpha)pyrene-exposed progeny.

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