MHC class I–deficient natural killer cells acquire a licensed phenotype after transfer into an MHC class I–sufficient environment

Abstract

In MHC class I–deficient hosts, natural killer (NK) cells are hyporesponsive to cross-linking of activation receptors. Functional competence requires engagement of a self–major histocompatability complex (MHC) class I–specific inhibitory receptor, a process referred to as “licensing.” We previously suggested that licensing is developmentally determined in the bone marrow. In this study, we find that unlicensed mature MHC class I–deficient splenic NK cells show gain-of-function and acquire a licensed phenotype after adoptive transfer into wild-type (WT) hosts. Transferred NK cells produce WT levels of interferon-γ after engagement of multiple activation receptors, and degranulate at levels equivalent to WT NK cells upon coincubation with target cells. Only NK cells expressing an inhibitory Ly49 receptor specific for a cognate host MHC class I molecule show this gain-of-function. Therefore, these findings, which may be relevant to clinical bone marrow transplantation, suggest that neither exposure to MHC class I ligands during NK development in the BM nor endogenous MHC class I expression by NK cells themselves is absolutely required for licensing.

Retuning of Mouse NK Cells after Interference with MHC Class I Sensing Adjusts Self-Tolerance but Preserves Anticancer Response

“…5), similar to the observations of Elliot and colleagues (26). As one possible explanation, we speculate that NKG2D modulation occurs continuously as a result of interactions between NK cells and surrounding cells (43).…”

“…Using MHC class I mosaic mice, we found that mature NK cells changed their reactivity when the surrounding MHC class I setup was altered in vitro (25). More recently, two groups reported a rapid adaptation in self-reactivity of NK cells after transfer to hosts with a novel MHC class I environment (26,27). These observations are in line with our proposal that NK cell education operates like a "rheostat" that continuously tunes the NK cell activation threshold (18).…”

“…While previous studies reported an increased in vitro responsiveness of NK cells after transfer, such alterations may reflect an increased activation status without a distinct functional consequence (26,27). In a clinical setting, this translates to transfer of hyporesponsive NK cells from a donor lacking a particular KIR ligand to a recipient where it is expressed, leading to rejection of recipient cancer cells with reduced MHC class I cells.…”

“…It was previously reported that this procedure can increase their in vitro responsiveness (26,27). Whether it also affects in vivo killing of tumor (or normal) cells is a critical question for immunotherapy that has not been investigated.…”

“…This is surprising given the strong rejection of normal cells that occurs when Ly49/MHC class I interactions are perturbed by MHC class I removal on the target cell (22,23). One explanation is that Ly49 receptor blockade affects the NK cell rheostat and thus retunes the activation threshold in NK cells to secure self-tolerance to normal cells (26,27). Furthermore, when KIR ligand-mismatched NK cells are transferred between individuals in NK cell therapy, the rheostat model predicts rapid induction of tolerance due to loss of appropriate HLA input.…”