Karre's “missing self” hypothesis posits that NK cells can recognize or “sense” the loss of MHC class I (or “self”) on potential target cells and become activated (1
). Over two decades of research has supported this hypothesis, with several studies convincingly showing that NK cells in wild-type mice are solely responsible for the rejection of MHC class I-deficient cells (2
). Interestingly, MHC class I-deficient animals (such as B2m−/−
, or H2-D−/−K−/−
mice) contain relatively normal numbers of NK cells (4
), yet do not succumb to autoimmunity. If NK cell-mediated rejection of MHC class I-deficient cells is indeed robust, why don't NK cells in the periphery of B2m−/−
mice target self-tissues for destruction? What are the regulatory mechanisms that keep NK cells in B2m−/−
mice in check?
Recent studies have suggested that NK cells undergo “licensing” or “disarming” in the bone marrow, a process that dictates the proper development of NK cells (8
). Immature NK cells expressing inhibitory receptors that can interact with their autologous MHC class I molecules go on to functional maturity. In the absence of these interactions, NK cells either fail to complete their maturation or are chronically stimulated, with either scenario resulting in hypo-responsive NK cells in the periphery (8
). Thus, these models predict that in mice lacking MHC class I, selective pressures ensure self-tolerance in developing NK cells that are unable to engage their inhibitory receptors.
Challenging the “licensing” and “disarming” models of NK cell unresponsiveness are studies showing robust NK cell activation and effector function in B2m−/−
mice following viral, bacterial, and parasite infections (8
). In this study, we addressed these issues by examining the phenotype and function of NK cells from B2m−/−
mice, either in non-infected or virus-infected animals. Furthermore, we generated mixed wild-type:B2m−/−
bone marrow chimeric mice in order to study the tolerance of wild-type NK cells to B2m−/−
host cells that are “missing self” in an environment where these NK cells were resting or activated by viral infection.