Inducible down-regulation of MHC class I results in natural killer cell tolerance

Natural killer (NK) cells are innate lymphocytes that are thought to kill cells that down-regulate MHC class I (MHC-I) through “missing-self” recognition. NK cells from B2m(−/−) mice that lack surface MHC-I, however, are not autoreactive as predicted by the missing-self hypothesis. As a result, it is unclear if MHC-I down-regulation in vivo induces NK cell reactivity or tolerance to missing-self. Here, we generated a floxed B2m mouse to acutely down-regulate MHC-I in vivo in a host that normally expresses MHC-I. Global down-regulation of MHC-I induced NK cell hyporesponsiveness and tolerance to missing-self without overt missing-self reactivity. In contrast, down-regulation of MHC-I on a small fraction of hematopoietic cells triggered missing-self reactivity. Surprisingly, down-regulation of MHC-I only on CD4(+) T cells predominately induced tolerance to missing-self without resetting NK cell responsiveness. In this setting, inflammation triggered substantial missing-self reactivity. These results show that MHC-I down-regulation can induce either NK cell tolerance or killing in vivo and that inflammation promotes missing-self reactivity.