Abstract
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.
Highlights
Leukocyte Ig-like receptors (LIR) regulate a diverse array of functions within the immune system (Colonna et al, 1999; Brown et al, 2004)
Typical natural killer (NK) cell profiles observed for our donors appeared biphasic, but with poor resolution of high and low expressing cells within the population, and often the LIR-1dim subset overlapping with isotype matched control
We have previously reported that the expression patterns of like receptor 1 (LIR-1) on NK cells in different individuals is linked to genetic variation within the LILRB1 gene (Davidson et al, 2010)
Summary
Leukocyte Ig-like receptors (LIR) regulate a diverse array of functions within the immune system (Colonna et al, 1999; Brown et al, 2004). The LIR family contains 11 functional members encoded within the Leukocyte Receptor Complex on human chromosome 19 (Wende et al, 1999). The LIR family includes both activating and inhibitory receptors, but the ligands and functions for many of these receptors have not yet been elucidated. Leukocyte Ig-like receptor 1 (LIR-1/ILT2/CD85j/LILRB1) is an inhibitory member of the Leukocyte Ig-like receptor family widely expressed in the immune system. The interaction with MHCI has been well characterized and involves the first and second Ig domains of LIR-1 making contact with highly conserved regions of the α3-domain and β2-microglobulin, thereby explaining its ability to bind to a wide range of MHC-I alleles (Chapman et al, 1999, 2000; Shiroishi et al, 2003). LIR-1 was reported to bind to several types of bacteria the details of this interaction and its role in infection remain to be determined (Nakayama et al, 2007)
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