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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 ...

Leukocyte Ig-like receptor 1 (LIR-1) is an inhibitory Ig superfamily receptor with broad specificity for MHC-I expressed on leukocytes including natural killer (NK) and T cells. The extent of LIR-1 expression on NK cells is quite disparate between donors but the regulation of LIR-1 in NK cells is poorly understood. We examined expression profiles of LIR-1 on NK and T lymphocytes in 11 healthy donors over 1 year. Four of the 11 donors demonstrated substantial increases in LIR-1+ NK cells. High levels of LIR-1 expression were not correlated with exposure to human cytomegalovirus or the fraction of CD57+ NK cells in the donor. LIR-1 levels on ex vivo NK and CD56+ T cells were increased in vitro by short term exposure to IL-2 or IL-15 compared to control but not with various other cytokines tested. Sorted CD56bright NK cells also increased LIR-1 expression when cultured in IL-2. Maintenance of LIR-1 on longer term NK cells was also dependent on continuous stimulation by IL-15 or IL-2. While we could not detect increases in total LIR-1 mRNA in response to cytokine treatment by qPCR, we observed a shift in activity of LIR-1 promoter reporter constructs in the presence of IL-2 favoring the more translationally active transcript from the proximal promoter. Together these results show LIR-1 on NK cells is under the control of cytokines known to drive NK cell maturation and activation and suggest availability of such cytokines may alter the NK repertoire in vivo as we observed in several donors with fluctuating levels of LIR-1 on their NK cells.