Object. Natural killer (NK) cell—mediated immunosurveillance in the brain is currently obscure, in contrast with the intracerebral immune reaction of cytotoxic T lymphocytes (CTLs) to tumor cells. The goal of this study, in which a controlled tumor model was used, was to investigate a relationship between NK cells and major histocompatibility complex (MHC) Class I gene expression in intracerebral tumor—bearing hosts.
Methods. A matched set of two cloned tumor cell lines (lymphoma+ and lymphoma−), which differ only in MHC Class I gene expression, was established from the parental YAC-1 cell line (a target widely accepted as being sensitive to murine NK cells). An in vivo rapid elimination assay (REA) was performed using tumor cells labeled with [125I] 5-iodo-2-deoxyuridine to evaluate intracerebral NK cell—mediated defense immunity. There was no difference in the in vitro growth rate and c-myc gene expression between lymphoma+ and lymphoma− cells. An in vitro cytotoxicity assay showed that the lymphoma+ cell line was sensitive to MHC Class I—restricted CTL-mediated lysis, whereas the lymphoma− line was refractory to it. Both were susceptible to NK cell—mediated lysis, comparable to the level shown by YAC-1 cells. Flow cytometry revealed that lymphoma+ reacted positively for cell-surface MHC Class I molecules, whereas lymphoma− had no reaction. Four- to 72-hour REAs, performed using either cell line, disclosed no clearance of radiolabeled tumor cells from the brain in independent groups of untreated and T cell—depleted mice; this contrasted with eradication of radioactivity from the lungs. In NK cell—depleted mice, however, there was no elimination of radiolabeled tumor cells from the brain or lungs. The MHC Class I expression on lymphoma+ cells was enhanced after intracerebral inoculation, rendering them less sensitive to NK cells. By contrast, lymphoma− cells remained negative for cell-surface MHC expression, being sensitive to NK cells and refractory to CTLs after intracerebral inoculation. These results indicate the absence of NK cell—mediated lytic activity in the brain. This allows even NK cell—sensitive tumor cells to escape intracerebral immunosurveillance.
Conclusions. These experiments have refined the information that the brain may lack NK cell—mediated defense immunity against intracerebrally growing tumors, representing a characteristic aspect of this immunologically privileged organ.
Cis- and trans-repression of class I major histocompatibility gene expression in Abelson virus-transformed murine leukemia
