Abstract
Immunosuppression is a typical hallmark of cancer and frequently includes perturbations of the NKG2D tumor recognition system as well as impaired signaling by other activating NK cell receptors. Several in vitro studies suggested that sustained engagement of the NKG2D receptor, as it is occurring in the tumor microenvironment, not only impairs expression and function of NKG2D but also impacts signaling by other activating NK receptors. Here, we made use of a transgenic mouse model of ubiquitous NKG2D ligand expression (H2-Kb-MICA mice) to investigate consequences of chronic NKG2D engagement in vivo for functional responsiveness by other activating NK receptors such as NKp46 and Ly49D. Unexpectedly, we found no evidence for an impairment of NKp46 expression and function in H2-Kb-MICA mice, as anticipated from previous in vitro experiments. However, we observed a marked downregulation and dysfunction of the activating receptor Ly49D in activated NK cells from H2-Kb-MICA mice. Ly49D shares the adaptor proteins DAP10 and DAP12 with NKG2D possibly explaining the collateral impairment of Ly49D function in situations of chronic NKG2D engagement. Altogether, our results demonstrate that persistent engagement of NKG2D in vivo, as often observed in tumors, can selectively impair functions of unrelated NK receptors and thereby compromise NK responsiveness to third-party antigens.
Highlights
Severe immunosuppression frequently occurs in patients with cancer [1, 2]
To investigate the impact of chronic NKG2D engagement on the NK cell compartment in vivo, we studied abundance, phenotype, and function of splenic NK cells from H2-Kb-MICA
As previously described [31], NKG2D receptors were profoundly downregulated on H2-Kb-MICA NK cells as a direct consequence of persistent engagement by ubiquitously expressed MICA*07 (Figure 1C)
Summary
Severe immunosuppression frequently occurs in patients with cancer [1, 2]. our knowledge of the underlying mechanisms is still incomplete. NK cells with their ability to recognize and kill malignant cells by the mechanisms of “missing-self ” recognition and “induced-self ” recognition play an important role in the immunosurveillance of cancer [3,4,5,6]. Inhibitory NK cell receptors specific for MHC class I molecules mediate “missing-self ” recognition by unleashing NK cell cytotoxicity against tumor cells having lost MHC class I surface expression [9]. In parallel, such an NK reactivity toward malignant cells must be triggered by activating NK cell receptors ligating cell surface molecules on tumor cells. Preferential NK cell recognition of tumor cells is achieved by activating NK cell receptors binding to molecules induced or upregulated in the course of malignant transformation (“induced-self ” recognition) [5, 6, 10]
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