Up on the tightrope: natural killer cell activation and inhibition

Abstract

Natural killer (NK) cells circulate through the blood, lymphatics and tissues, on patrol for the presence of transformed or pathogen-infected cells. As almost all NK cell receptors bind to host-encoded ligands, signals are constantly being transmitted into NK cells, whether they interact with normal or abnormal cells. The sophisticated repertoire of activating and inhibitory receptors that has evolved to regulate NK cell activity ensures that NK cells protect hosts against pathogens, yet prevents deleterious NK cell-driven autoimmune responses. Here I highlight recent advances in our understanding of the structural properties and signaling pathways of the inhibitory and activating NK cell receptors, with a particular focus on the ITAM-dependent activating receptors, the NKG2D-DAP10 receptor complexes and the CD244 receptor system. NK cells, like other members of the innate immune system, were once considered nonspecific in their interactions with tumors or virus-infected cells. A seminal study noted that NK cells can kill certain tumor cells lacking MHC class I, yet spare the same tumors expressing MHC class I (ref. 1). This ability to attack cells 'missing self' predicted the existence of inhibitory receptors on NK cells, and it revealed the mechanism whereby NK cells engage in surveillance for transformed or virus-infected cells that have downregulated expression of MHC class I in an effort to avoid recognition by CD8 + cytotoxic T lymphocytes. However, missing from the missing-self hypothesis was any molecular basis for how NK cells are activated when they encounter tumors or virus-infected cells, or how in certain circumstances NK cells do efficiently recognize and kill tumors or virus-infected cells that maintain expression of MHC class I. Even after the discovery of the inhibitory NK cell receptors, activation of NK cells against MHC class I-deficient cells was generally considered nonspecific. Not so anymore. Many activating NK cell receptors and pathways have recently been identified, and the interplay between the inhibitory receptors and activating receptors are being defined. This review highlights the predominant signaling pathways that regulate the responses of NK cells encountering potential target cells. Inhibitory NK receptorsNK cells express a repertoire of inhibitory receptors that regulate their activation. Some inhibitory NK receptors are specific for MHC class I, whereas others bind non-MHC ligands (Supplementary Table 1 online). Some of these inhibitory NK receptors, such as killer cell immunoglobulin-like receptors (KIRs) and leukocyte immunoglobulin-like receptors (LILRs), are monomeric type I glycoproteins of the immunoglobulin superfamily, whereas others, suchCorrespondence should be addressed to L.L.L. (E-mail: lewis.lanier@ucsf.edu).. Note: Supplementary information is available on the Nature Immunology website. COMPETING INTERESTS STATEMENTThe author declares competing financial interests: details accompany the full-text HTML version of the paper at http://www.nature.com/natur...

PGE2 inhibits natural killer and γδ T cell cytotoxicity triggered by NKR and TCR through a cAMP-mediated PKA type I-dependent signaling

“…To our knowledge, this is the first report demonstrating that the activation of PKA type I mediated by Like TCR, NCR and CD16 are associated with adapter proteins (such as CD3, DAP12 and FcRI-) which bear Immunoreceptor Tyrosine-based Activating Motifs (ITAM) and recruit the tyrosine kinases ZAP70 and Syk [35]. In contrast, NKG2D is associated with the adapter protein DAP10 which contains an YINM motif and recruits the adapter Grb2 and the kinase PI3K [36,37].…”

“…In contrast, NKG2D is associated with the adapter protein DAP10 which contains an YINM motif and recruits the adapter Grb2 and the kinase PI3K [36,37]. All these adapter proteins need to be phosphorylated by kinases of the Src family (such 18 as Lck) to transmit their activating signal [35]. We show that cAMP and PKA type I are both implicated in the inhibition of NCR, CD16 and NKG2D by PGE 2 suggesting that, like  and V9V2 TCR, blockade by PGE 2 is dependent on the inactivation of Lck mediated by Csk.…”

“…We show that cAMP and PKA type I are both implicated in the inhibition of NCR, CD16 and NKG2D by PGE 2 suggesting that, like  and V9V2 TCR, blockade by PGE 2 is dependent on the inactivation of Lck mediated by Csk. Other kinases of the Src family such as Fyn, Src, Yes and Lyn are also expressed in NK cells and might have redundant functions with Lck [35]. It remained to be determined if these Src kinases are also targeted by the activation of PKA type I mediated by PGE 2 .…”

NCR+ILC3 concentrate in human lung cancer and associate with intratumoral lymphoid structures

“…Natural killer (NK) cells, the first ILC discovered and the most widely distributed in different tissues, are regulated through a variety of activating and inhibitory cell surface receptors [3][4][5] . Current data are compatible with the concept that the ligands for activating NK receptors are expressed primarily by 'stressed' cells (including tumour or virus-infected cells).…”

NK cells from tuberculous pleurisy express high ICAM‐1 levels and exert stimulatory effect on local T cells

“…This pleural effusion is characterized by a strong granulomatous inflammatory response to Mtb together with high levels of . NK cells are CD56 1 CD16 1/À /CD3 À CD19 À lymphocytes of the innate immune system whose function is controlled by an array of germline-encoded activator/inhibitory receptors [5,6]. Two subsets of NK cells have been identified in humans according to CD56 expression differing in phenotype and function, and also in terms of chemokine receptors and adhesion molecules expression [7,8,9].…”