Activating and inhibitory receptors of natural killer cells

Abstract

Natural killer (NK) cells are potent immune effector cells that can respond to infection and cancer, as well as allowing maternal adaptation to pregnancy. In response to malignant transformation or pathogenic invasion, NK cells can secrete cytokine and may be directly cytolytic, as well as exerting effects indirectly through other cells of the immune system. To recognize and respond to inflamed or infected tissues, NK cells express a variety of activating and inhibitory receptors including NKG2D, Ly49 or KIR, CD94-NKG2 heterodimers and natural cytotoxicity receptors, as well as co-stimulatory receptors. These receptors recognize cellular stress ligands as well as major histocompatibility complex class I and related molecules, which can lead to NK cell responses. Importantly, NK cells must remain tolerant of healthy tissue, and some of these receptors can also prevent activation of NK cells. In this review, we describe the expression of prominent NK cell receptors, as well as expression of their ligands and their role in immune responses. In addition, we describe the main signaling pathways used by NK cell receptors. Although we now appreciate that NK cell biology is more complicated than first thought, there are still facets of their biology that remain unclear. These will be highlighted and discussed in this review.

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“…NK cell cytotoxic activity is regulated by the integration of signals from inhibitory and activating receptors (32). Of particular interest is the activating receptor NKG2D, which binds to several cell surface glycoproteins in mice, including the RAE-1 proteins and the minor histocompatibility Ag H-60 (33).…”

T-cell and natural killer cell therapies for hematologic malignancies after hematopoietic stem cell transplantation: enhancing the graft-versus-leukemia effect

“…A balance of these opposing signals determines whether NK cells exert their powerful activities or remain tolerant (Figure 4). 80 The absence of a corresponding matched inhibitory ligand, for example, is often enough signal for the NK cell to eliminate the defective target (the "missing self" hypothesis of NK cell activation). 81 But in a remarkable evolutionary design, only NK cells with inhibitory receptors that have previously encountered self ligands (from interacting with their own hematopoietic cells) are "licensed" to kill non-self-expressing target cells.…”

Functional characterization of a conserved pair of NKR‐P1 receptors expressed by NK cells and T lymphocytes in liver and gut

“…Both the Ly49 and NKG2/CD94 receptor families contain inhibitory and activating members. NKG2D is a promiscuous activating receptor, recognizing several MHC class I-related ligands frequently upregulated upon cellular stress and associated with viral infection and malignant transformation [8].The activating NK cytotoxicity receptors react with several virus-derived and endogenous ligands [9,10].One of the earliest NK-cell receptors to be characterized was the NK-cell receptor protein 1A (NKR-P1A) in the rat, which is C 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu …”