Lack of expression of inhibitory KIR3DL1 receptor in patients with natural killer cell-type lymphoproliferative disease of granular lymphocytes

Abstract

BACKGROUND:Natural killer cell-type lymphoproliferative disease of granular lymphocytes is a disorder characterized by chronic proliferation of CD3(-)CD16(+) granular lymphocytes. By flow cytometry analysis, we previously demonstrated a dysregulation in killer immunoglobulin-like receptor (KIR) expression in natural killer cells from patients with this lymphoproliferative disease, the activating KIR receptors being mostly expressed. We also found that patients with natural killer cell-type lymphoproliferative disease of granular lymphocytes usually had KIR genotypes characterized by multiple activating KIR genes.DESIGN AND METHODS:We investigated the mRNA levels of the KIR3DL1 inhibitory and the related KIR3DS1 activating receptors in 15 patients with natural killer cell-type lymphoproliferative disease of granular lymphocytes and in ten controls. These genes are usually expressed when present in the genome of the Caucasian population.RESULTS: We demonstrated the complete lack of KIR3DL1 expression in most of the patients analyzed, with the receptor being expressed in 13% of patients compared to in 90% of controls (P<0.01). Interestingly, studies of the methylation patterns of KIR3DL1 promoter showed a significantly higher methylation status (0.76 ± 0.12 SD) in patients than in healthy subjects (0.49±0.10 SD, P<0.01). The levels of expression of DNA methyl transferases, which are the enzymes responsible for DNA methylation, did not differ between patients and controls.CONCLUSIONS:In this study we showed, for the first time, a consistent down-regulation of the inhibitory KIR3DL1 signal due to marked methylation of its promoter, thus suggesting that together with the increased expression of activating receptors, the lack of the inhibitory signal could also play a role in the pathogenesis of natural killer cell-type lymphoproliferative disease of granular lymphocytes

Detection of monoclonal T populations in patients with KIR-restricted chronic lymphoproliferative disorder of NK cells

“…In fact, NK cells equipped with an activating KIR gene aplotype are thought to be more prone to clonal expansion, with a concomitant marked silencing of inhibitory KIRs. 9,10,32 The selection of T cells during the T-LGLL pathogenesis has been more precisely investigated. T-LGL cells exhibit the activation of multiple survival signaling pathways, 33 are characterized by the failure to undergo AICD, 11 and are not sensitive to Fasinduced apoptosis.…”

“…This impaired expression of inhibitory receptors is dependent on the patient's genotype, and is characterized by the presence of multiple activating KIR genes 9 and on a discrete silencing of inhibitory KIR genes through their promoter methylation. 10 On the other hand, attempts to understand the pathogenesis of T-LGLL have suggested there is a crucial role for inflammatory cytokines. Leukemic T-LGLs fail to undergo activationinduced cell death (AICD), an event that is consequent to a critical impairment of Fas-induced apoptosis.…”

Physiological and Pathological Aspects of Human NK Cells

“…A typical feature is the preferential expression of the KIR activating receptor isoforms and this pattern correlates with a reduced expression of other activating receptors, such as NCRs . Together with a bias towards activating KIR expression, a deep silencing of inhibitory KIR through increased gene methylation has been recently demonstrated by our group (Gattazzo et al, 2010). More specifically, we showed the complete lack of KIR3DL1 expression in most analyzed patients, being the receptor expressed in 13% of patients as compared to 90% of controls (p<0.01).…”

“…Interestingly, the results of methylation patterns of KIR3DL1 promoter showed a significantly higher methylation status (0.76 ± 0.12 SD) in the patients with respect to the healthy subjects (0.49 ± 0.10 SD, p<0.01). These data suggest that together with the increased expression of activating receptors, the lack of the inhibitory signal could also play a role in the pathogenesis of disease (Gattazzo et al, 2010). Recent data on the pathogenesis of CLPD-NK are summarized in Figure 2.…”

“…Patients are usually adults with a mean age of 60 years without gender and racial predisposition (Pandolfi et al, 1990). In recent years several studies have been published focusing on the pathogenetic mechanisms of this disease Loughran et al, 1997;Hodge et al, 2009;Gattazzo et al, 2010;Epling-Burnette et al, 2008). NK cell activation in response to an unknown stimulus, likely of viral origin, is postulated to play a role in the initial steps of CLPD-NK by selecting NK clones .…”