NKG2D in Tumor and Graft Surveillance

Abstract

Natural killer (NK) cells are involved in graft rejection and may contribute to tumor recognition and elimination. Ogasawara et al. report that increased production of NKG2D ligands may be one mechanism by which certain tissues are prone to graft rejection and that antibodies against NKGD2 can prevent rejection in these cases. Oppenheim et al. report that localized high expression of NKG2D ligands inhibited NK cell function, contributing to evasion of the immune system by tumors. To study graft rejection, Ogasawara et al. evaluated NKG2D ligand expression (by antibody staining) of bone marrow cells from BALB/C or C57BL/6 mice that were transplanted into irradiated F 1 progeny from a BALB/C C57BL/6 cross, an example of F 1 hybrid resistance. The BALB/C cells expressed the ligand Rae-1 and were rejected by the F1 progeny mice. The C57BL/6 mouse cells were also rejected, but they did not express any NKG2D ligands; thus, there are at least two mechanisms for NK cell-mediated rejection. Depletion of the NK cells from the recipient mice allowed the transplanted cells from both parental strains to survive; however, only in the case of the BALB/C transplanted cells did neutralizing antibodies to NKG2D increase the incorporation of the transplanted cells in the spleens of the recipient mice. The Rae-1 ligand was also the focus of the studies by Oppenheim et al. In this case, two kinds of transgenic mice were generated: those expressing Rae-1ε in squamous epithelium only (lines 110 and 121) and those expressing Rae-1ε ubiquitously (line 187). Both types of transgenic mice showed decreased abundance of NKG2D-positive NK cells; however, the abundance of other proteins (such as CD94) typically expressed by this population of NK cells was normal. Thus, the NKG2D receptor itself appeared to be down-regulated rather than the cell population depleted. Coculturing of NKG2D-positive splenocytes with the splenocytes from the 187 line (high Rae-11ε) resulted in loss of NKG2D from the nontransgenic cells. Injection of a mixture of splenocytes from the 187 line and control splenocytes into control mice or transgenic mice showed that clearance of the Rae-1-positive cells was impaired in the transgenic mice. Activation of the NK cells with poly (I:C) restored killing of the Rae-1-positive cells in the epithelial transgenic mice only, suggesting that a residual population of NKG2D-positive cells could be rescued in the 110 and 121 lines. Finally, the transgenic mice showed increased susceptibility to tumorigenesis (chemical induced and injection of tumor cells). Thus, the NKG2D receptor is a critical player in tumor surveillance and graft rejection. K. Ogasawara, J. Benjamin, R. Takaki, J. H. Phillips, L. L. Lanier, Function of NKG2D in natural killer cell-mediated rejection of mouse bone marrow grafts. Nat. Immunol. 6 , 938-945 (2005). [Online Journal] D. E. Oppenheim, S. J. Roberts, S. L. Clarke, R. Filler, J. M. Lewis, R. E. Tigelaar, M. Girardi, A. C. Hayday, Sustained localized expression of ligand for the activating NKG2D receptor impairs natural cytotoxicity in vivo and reduces tumor surveillance. Nat. Immunol. 6 , 928-937 (2005). [Online Journal]