The Inhibitory Receptor NKG2A Determines Lysis of Vaccinia Virus-Infected Autologous Targets by NK Cells

Abstract

Signals transduced by inhibitory receptors that recognize self-MHC class I molecules prevent NK cells from being activated by autologous healthy target cells. In order for NK cells to be activated upon contact with an infected cell, the balance between the activating and inhibitory signals that regulate NK cell function must be altered in favor of activation. By studying liver-derived NK cells, we show that only a subpopulation of NK cells expressing high levels of the inhibitory receptor NKG2A are able to lyse autologous vaccinia-infected targets, and that this is due to selective down-regulation of HLA-E. These data demonstrate that release from an inhibitory receptor:ligand interaction is one mechanism that permits NK cell recognition of a virally infected target, and that the variegated expression of inhibitory receptors in humans generates a repertoire of NK cells with different antiviral potentials.

Critical and Differential Roles of NKp46- and NKp30-Activating Receptors Expressed by Uterine NK Cells in Early Pregnancy

“…Thus, a likely explanation is that dNK cells might be an important component of the local innate immune response to uterine virus infection, through specific ligand triggering of NKp46 (and possibly other coactivating receptors) that would be dominant over NKG2A-mediated inhibitory signals. NK cell inhibitory receptors are indeed targeted by viral immune evasion strategies (23,39), which may lead to the absence or diminished expression of HLA-E-specific ligand (40). Some virus-infected cells might also be recognized by the NKp46 receptor through the binding of viral hemaglutinin (41) or as-yet undefined protein ligand, leading to the killing of these infected target cells.…”

“…Such specific interactions lead to secretion of IL-8/IP10 chemokines attracting trophoblast, vascular endothelial growth factor/placental growth factor angiogenic factors which in turn control the uterine vascular remodeling (35), and likely several additional inflammatory cytokines (this study). In the case of uterine infection, NKG2A-mediated negative signals controlling NKp46-mediated cytolytic function might be abrogated by some viral immune evasion mechanisms, leading to the absence or diminished expression of its HLA-E-specific ligand (40) and the upregulation of the NKp46 specific ligand. Such NKp46-mediated cytotoxic activity together with the NKp30-mediated secretion of inflammatory cytokines by dNK may thus contribute to the drop in the number of uterine infected cells.…”

Regulation of Activated CD4+ T Cells by NK Cells via the Qa-1–NKG2A Inhibitory Pathway

“…It may be relevant that human NK cells clones from hepatitis C virus-infected human liver are divisible into functionally distinct subsets according to NKG2A expression. NKG2A + but not NKG2A À NK clones lyse vaccinia-infected autologous BLCL cells, while both NKG2A + and NKG2A À clones lyse a MHC class I-negative parent BLCL cell line (Brooks et al, 2006). Although NK cells from DBA/2J mice are naturally CD94 deficient, a preliminary analysis of NK cells from DBA/ 2Ncr (CD94:NKG2A + ) and DBA/2J (CD94:NKG2A À ) failed to show a difference in NK lytic activity against autologous activated CD4 + T cells in the presence of Qa-1 antibody (not shown).…”

Synergistic inhibition of natural killer cells by the nonsignaling molecule CD94

“…Expression of CD94-NKG2A is up-regulated on NK cells in HIV and HCV infection and in the latter has been associated with a poor response to treatment (11,12). Furthermore NKG2A + NK cell clones lyse vaccinia-infected targets (13), and CD94 is important in clearing mouse pox infection (14). Both KIR and CD94-NKG2A respond to MHC class I down-regulation.…”