A Role for cis Interaction between the Inhibitory Ly49A Receptor and MHC Class I for Natural Killer Cell Education

Chalifour, Anick; Scarpellino, Léonardo; Back, Jonathan; Brodin, Petter; Devêvre, Estelle; Gros, Frédéric; Lévy, Frédéric; Leclercq, Georges; Höglund, Petter; Beermann, Friedrich; Held, Werner

doi:10.1016/j.immuni.2008.12.019

Cited by 121 publications

(148 citation statements)

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“…This unexpected finding indicates that several mechanisms may control repertoire formation in response to MHC class I. It has been proposed that interactions between MHC class I and Ly49 receptors can occur in trans (between NK cells and other cells) as well as in cis (in the NK cell membrane itself) (32,33). One possibility is that the general shift in the repertoire toward few receptors results from MHC interactions in trans by the educating environment.…”

Section: Discussionmentioning

confidence: 99%

Skewing of the NK Cell Repertoire by MHC Class I via Quantitatively Controlled Enrichment and Contraction of Specific Ly49 Subsets

Brodin

Lakshmikanth

Kärre

et al. 2012

The Journal of Immunology

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A major task for the immune system is to secure powerful immune reactions while preserving self-tolerance. This process is particularly challenging for NK cells, for which tolerizing inhibitory receptors for self-MHC class I is both cross-reactive and expressed in an overlapping fashion between NK cells. We show in this study that during an education process, self-MHC class I molecules enrich for potentially useful and contract potentially dangerous NK cell subsets. These processes were quantitatively controlled by the expression level of the educating MHC class I allele, correlated with susceptibility to IL-15 and sensitivity to apoptosis in relevant NK cell subsets, and were linked to their functional education. Controlling the size of NK cell subsets with unique compositions of inhibitory receptors may represent one mechanism by which self-MHC class I molecules generate a population of tolerant NK cells optimally suited for efficient missing self-recognition.

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Section: Discussionmentioning

confidence: 99%

Skewing of the NK Cell Repertoire by MHC Class I via Quantitatively Controlled Enrichment and Contraction of Specific Ly49 Subsets

Brodin

Lakshmikanth

Kärre

et al. 2012

The Journal of Immunology

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“…Interestingly, in the murine system the interactions of Ly49A and MHC-I occur with identical specificity in both cis and trans, implying that the region of Ly49A that makes contact is the same in either case. Moreover, Ly49 constructs with shortened stalks appear able to function only in trans, suggesting the extension by the stalk is required to reach the MHC-I in cis, and that the cis and trans interactions are mediated by two distinct conformations of the receptor [30]. The long extracellular stalk region provides Ly49A with the flexibility necessary to mediate interactions with MHC-I in cis.…”

Section: Discussionmentioning

confidence: 99%

“…Inhibitory receptors bound in cis could potentially serve as a rheostat-like control mechanism to regulate the inhibitory input received by an NK cell in order to optimize activation efficiency. In mice it was reported that antibody-mediated sequestration of Ly49A, which mimics receptor sequestration by MHC-I in cis, can enhance the function of mature NK cells triggered via activating receptors [30]. During NK-cell development, a rheostat model has been proposed, where the inhibitory input an NK cell receives during education directly adjusts the efficiency of activation pathways in signaling responses [34,35].…”

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confidence: 99%

“…During NK-cell development, a rheostat model has been proposed, where the inhibitory input an NK cell receives during education directly adjusts the efficiency of activation pathways in signaling responses [34,35]. Additionally, the cis interaction of inhibitory receptors was demonstrated to significantly contribute to NK-cell development in mice, as a Ly49A variant that is unable to engage MHC-I in cis failed to educate NK cells, despite maintaining the ability to signal in trans [30]. However, it was reported that LIR-1 single positive NK cells did not exhibit enhanced missing-self responses relative to KIR positive subsets, and were functionally comparable to "receptor-null" cells, suggesting LIR-1 expression alone is not sufficient for education [36].…”

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confidence: 99%

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Cis association of leukocyte Ig‐like receptor 1 with MHC class I modulates accessibility to antibodies and HCMV UL18

Uchtenhagen

et al. 2013

Eur J Immunol

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IntroductionNK cells are cytotoxic lymphocytes of the immune system, which provide innate protection against viral infection and tumor transformation [1]. NK cells eliminate altered self-cells through the direct recognition and subsequent lysis of engaged targets. The effector functions of these immune cells are dynamically regulated through the coordinated signaling of cell surface receptors that either activate or inhibit responses [2]. The stimulatory Correspondence: Dr. Deborah N. Burshtyn e-mail: burshtyn@ualberta.ca NK-cell receptors signal through coupled adaptor proteins that encode cytoplasmic ITAMs [3]. Conversely, the inhibitory receptors dampen NK-cell responses via long cytoplasmic tails encoding ITIMs, which recruit SH2 domain-containing phosphatases such as SHP-1 following tyrosine phosphorylation [4]. The inhibitory receptors typically recognize MHC class I (MHC-I) molecules, and therefore healthy self-cells expressing a full complement of MHC-I are protected from NK-cell lysis. NK cells thus sense the density of ligands on engaged cells, and it is the balance of signals received through these functionally opposing receptors that ultimately determines both the response of the effector cell and the fate of the target cell.Inhibitory MHC-I receptors expressed on human NK cells include the killer cell Ig-like receptors (KIRs) and leukocyte Ig-like C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2013. 43: 1042-1052 Molecular immunology 1043 receptor-1 (LIR-1), which are encoded on chromosome 19q13.4 within the leukocyte receptor complex [5]. The LIR family encodes receptors with either two or four Ig domains and includes both inhibitory and activating members. While the ligands for all LIR family members have not yet been identified, the inhibitory members LIR-1 and LIR-2 bind MHC-I at the relatively conserved α3 domain and β 2 -microglobulin, allowing for broad specificity and recognition of both classical and nonclassical molecules [6,7]. NK-cell expression of LIR-1 varies between individuals and mediates inhibition of NK cells in response to MHC-I, particularly 9]. LIR-1 is also targeted by a virally encoded MHC-I homologue known as UL18 [10], which shares approximately 25% amino acid sequence identity with MHC-I and associates with human β 2 -microglobulin [11,12]. UL18 binds to LIR-1 with more than 1000-fold greater affinity than MHC-I molecules [7,13,14] and has been shown to mediate suppression of LIR-1 + NK cells in vitro [15]. Studies of LIR-1 function to date have primarily focused on the interaction of the receptor with its ligand in trans, such as inhibition of NK or T cells through recognition of a ligand expressed on a target cell or APC [16][17][18][19][20][21]. However, there is mounting evidence that the interaction of these immune receptors with ligands on the same cell, or in cis, influence how they function [22]. In the murine system, the cis interaction of MHC-I specific NK-cell receptors plays a key role in regulating NK-cell responses. The ...

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“…Since in our system cytokine stimulation can confer competence in the absence of any accessory cells, KIR could engage the cognate MHC molecule expressed on the same NK cell (cis interaction) or on neighboring NK cells (trans interaction). In mice it has been recently shown that cis interaction between inhibitory Ly49A receptor and MHC class I plays a role for education of NK cells [15]. Although the hypothesis that human NK-cell education as well is mediated via cis interaction would be very attractive, there is currently no evidence that the function of KIR is influenced by HLA expression in cis [16].…”

Section: Discussionmentioning

confidence: 99%

Education of hyporesponsive NK cells by cytokines

et al. 2009

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NK-cell tolerance to self is mediated via engagement of inhibitory receptors by cognate MHC molecules. This event is critical for NK-cell education to achieve functional competence. Thus, NK cells expressing self-MHC-specific inhibitory receptors are responsive to activating stimuli while those lacking such receptors are hyporesponsive. Nevertheless, the mechanisms underlying NK-cell education are still poorly understood. Here, we show that after stimulation with cytokines, hyporesponsive NK cells acquire stable expression of killer Ig-like receptors (KIR) as reflected by DNA hypomethylation of their KIR locus. Remarkably, only hyporesponsive NK cells that acquire KIR in the presence of their cognate MHC molecule gain functional competence and this process can occur in the absence of any accessory cells. Acquisition of competence does not result in autoreactivity, since acquired KIR are functional and therefore able to inhibit NK-cell cytotoxicity. Our data demonstrate that competent NK cells can be generated by cytokine stimulation, suggesting that NK-cell education might not only be an early event which takes place during NK-cell development but might also occur in the periphery during an immune response.Key words: Education . Killer Ig-like receptors . MHC . NK cells . Tolerance Supporting Information available onlineIntroduction NK cells are bone-marrow derived lymphocytes which play an important role in mediating innate immune responses to viruses, tumors and MHC-mismatched bone marrow grafts. The main effector functions of NK cells, such as cytokine production and cytotoxicity, are tightly regulated by a balance between activating and inhibitory signals. After engagement of multiple activating receptors expressed on their surface, NK cells can produce IFN-g and kill target cells. In most cases, ligands for activating receptors are pathogen-encoded molecules or self-proteins whose expression is up-regulated in transformed or infected cells. However, even normal cells can be lysed by NK cells if they fail to express a full set of self-MHC class I proteins [1]. These observations highlight NK-cell potential autoreactivity and raise the question of how NK cells discriminate diseased cells from healthy ones. NK cells are self-tolerant because they express inhibitory receptors specific for distinct polymorphic variants of MHC class I molecules which counteract the activating signals. Inhibitory receptors include the killer Ig-like receptors (KIR) in humans, the lectin-like Ly49 dimers in mice and the lectin-like CD94/NKG2A heterodimers in both species. Interestingly, the genes for inhibitory receptors and their cognate MHC class I ligands segregate independently, so genetic mechanisms cannot ensure that each NK-cell inhibitory receptor encounters its specific self-MHC class I molecule [2]. In line with this fact, some NK cells exist, which do not express any self-MHC class I-specific inhibitory receptor. However, 2548such NK cells are self-tolerant because they are hyporesponsive after engagement of activating ...

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A Role for cis Interaction between the Inhibitory Ly49A Receptor and MHC Class I for Natural Killer Cell Education

Cited by 121 publications

References 42 publications

Skewing of the NK Cell Repertoire by MHC Class I via Quantitatively Controlled Enrichment and Contraction of Specific Ly49 Subsets

Skewing of the NK Cell Repertoire by MHC Class I via Quantitatively Controlled Enrichment and Contraction of Specific Ly49 Subsets

Cis association of leukocyte Ig‐like receptor 1 with MHC class I modulates accessibility to antibodies and HCMV UL18

Education of hyporesponsive NK cells by cytokines

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