Controlling Natural Killer Cell Responses: Integration of Signals for Activation and Inhibition

Abstract

Understanding how signals are integrated to control NK cell responsiveness in the absence of antigen-specific receptors has been a challenge, but recent work has revealed some underlying principles that govern NK cell responses. NK cells use an array of innate receptors to sense their environment and respond to alterations caused by infections, cellular stress and transformation. No single activation receptor dominates; instead, synergistic signals from combinations of receptors are integrated to activate natural cytotoxicity and cytokine production. Inhibitory receptors for MHC class I have a critical role in controlling NK cell responses and paradoxically, in maintaining NK cells in a state of responsiveness to subsequent activation events, a process referred to as licensing. MHC-I specific inhibitory receptors both block activation signals and trigger signals to phosphorylate and inactivate the small adaptor Crk. These different facets of inhibitory signaling are incorporated into a revocable license model for the reversible tuning of NK cell responsiveness.

Intrinsic Functional Potential of NK-Cell Subsets Constrains Retargeting Driven by Chimeric Antigen Receptors

“…Thus, it remains unknown how repertoire diversity within the NK-cell compartment might influence the functional potential of CAR-redirected NK cells. NK cells are controlled by the integration of signals from activating and inhibiting receptors; the inhibiting receptors dominate (19). Inhibitory receptors include the killer cell immunoglobulin-like receptor (KIRs) and CD94/NKG2A.…”

Nidogen-1 is a novel extracellular ligand for the NKp44 activating receptor

“…1-9 In order to fulfill this variety of functions, NK cells use an array of receptors which sense microenvironmental stimuli and mediate appropriate responses. 3,10,11 Several NK receptors are capable of regulating different NK cell functions. For example, the Natural Cytotoxicity Receptors (NCRs) NKp46, NKp30, and NKp44, play an important role in human NK cell-mediated recognition and killing of virally infected and tumor cells, and also induce the release of a number of cytokines and chemotactic factors.…”

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

“…They kill virus-infected or transformed cells and secrete cytokines that regulate other immune responses (1). NK cell activation is mediated by germline encoded receptors that bind to ligands expressed by normal and malignant cells (2,3). Activation is balanced by inhibitory MHC class I-specific receptors: killer cell immunoglobulin-like receptors (KIR) in humans, Ly49 in mice, and NKG2A/CD94 receptors expressed in both species (2).…”

“…NK cell activation is mediated by germline encoded receptors that bind to ligands expressed by normal and malignant cells (2,3). Activation is balanced by inhibitory MHC class I-specific receptors: killer cell immunoglobulin-like receptors (KIR) in humans, Ly49 in mice, and NKG2A/CD94 receptors expressed in both species (2). The presence of inhibitory MHC class I-specific receptors allows NK cells to react to "missing self," i.e., insufficient amounts of self MHC class I on target cells (4,5).…”