Both the nature of KIR3DL1 alleles and the KIR3DL1/S1 allele combination affect the KIR3DL1 NK‐cell repertoire in the French population

Abstract

NK-cell functions are regulated by many activating and inhibitory receptors including KIR3DL1. Extensive allelic polymorphism and variability in expression can directly alter NK-cell phenotype and functions. Here we investigated the KIR3DL1+ NK-cell repertoire, taking into account the allelic KIR3DL1/S1 polymorphism, KIR3DL1 phenotype, and function. All 109 studied individuals possessed at least one KIR3DL1 allele, with weak KIR3DL1*054, or null alleles being frequently present. In KIR3DL1 high/null individuals, we observed a bimodal distribution of KIR3DL1 + NK cells identified by a different KIR3DL1 expression level and cell frequency regardless of a similar amount of both KIR3DL1 transcripts, HLA background, or KIR2D expression. However, this bimodal distribution can be explained by a functional selection following a hierarchy of KIR3DL1 receptors. The higher expression of KIR3DL1 observed on cord blood NK cells suggests the expression of the functional KIR3DL1*004 receptors. Thus, the low amplification of KIR3DL1 high , KIR3DL1*004 NK-cell subsets during development may be due to extensive signaling via these two receptors. Albeit in a nonexclusive manner, individual immunological experience may contribute to shaping the KIR3DL1 NK-cell repertoire. Together, this study provides new insight into the mechanisms regulating the KIR3DL1 NK-cell repertoire.Keywords: Allelic polymorphism · French population · KIR3DL1 · KIR3DL1/S1 allele combinations · NK-cell repertoire Additional supporting information may be found in the online version of this article at the publisher's web-site [10]. Within the human population, genomic diversity of the KIR region is achieved on several levels. KIR gene content varies between individuals who can exhibit 7-14 inhibitory and activating KIR genes [11]. Population studies have demonstrated two major KIR haplotypes: A and B [12]. The A haplotypes correspond to 7 KIR genes, including KIR2DS4 as the only activating KIR gene. In contrast, B haplotypes are more diverse and are characterized by the presence of more than one activating KIR gene and the absence of the KIR2DS4 gene [13,14]. KIR gene polymorphism is the largest contributor to KIR region diversity, with multiple alleles defined [15]. While polymorphism is limited in the KIR2DL1 and KIR2DL2/L3 genes, it is much broader for KIR3DL1 and can even alter NK-cell functions [16,17]. Indeed, depending on the KIR3DL1 allele present in a given individual, the level of KIR3DL1 expression differs on the NK-cell surface, i.e. null for KIR3DL1*004, low for KIR3DL1*005 and *007, and high for KIR3DL1*001, *002, *01502, and *008 alleles [18][19][20]. Two KIR3DL1 alleles can be transcribed in one NK-cell clone, and the proportion of clones expressing both alleles is high in comparison to clones expressing only one KIR3DL1 allele. However, based on the phenotypic pattern on all NK cells, only the nature of each allele is marked [19].In addition to allelic polymorphism, the variability in expression levels of KIR3DL1 molecules on the NK-cell surf...

Large Spectrum of HLA-C Recognition by Killer Ig–like Receptor (KIR)2DL2 and KIR2DL3 and Restricted C1 Specificity of KIR2DS2: Dominant Impact of KIR2DL2/KIR2DS2 on KIR2D NK Cell Repertoire Formation

“…Thus, the formation of the KIR2D NK repertoire is probably finely adjusted depending on the KIR2DL polymorphism and on the other NK cell subsets. In this regard, we have recently shown the impact of KIR3DL1 allelic nature on KIR3DL1 NK repertoire formation (37). These recent investigations suggest primary expression of KIR3DL1 followed by KIR2D acquisition.…”

KIR and HLA Genotypes Predictive of Low-Affinity Interactions Are Associated with Lower Relapse in Autologous Hematopoietic Cell Transplantation for Acute Myeloid Leukemia

“…Emerging data suggest that two polymorphisms within the KIR3DL1*004 allele (Leu 86 and Ser 182 ) negatively affect protein folding, resulting in significantly reduced cell surface expression (18,61,(65)(66)(67). NK cells dimly expressing the KIR3DL1*004 (71,72). Simple dichotomies in NK cell receptor-ligand binding affinities and definitions of cognate KIR-ligand interactions have also been questioned and further limit our ability to predict in vivo NK cell function (20,73).…”

Use of killer cell immunoglobulin-like receptor genes as early markers of hematopoietic chimerism after double-umbilical cord blood transplantation

“…9 For some dUCBT, KIR genotyping with an INVITROGEN kit was performed to allow the assessment of KIR2DL5 alleles and KIR3DL1 alleles were assigned as already reported. 8 KIR genes involved in the evaluation of chimerism status are highlighted in black boxes. Results indicate full donor chimerism from UCB 1.…”

“…Natural killer (NK) cells are the first population to reconstitute the patient's hematopoietic system following hematopoietic stem cell transplantation, before T lymphocytes, 7 and we previously reported that cord blood NK cells express killer cell immunoglobulin-like receptors (KIR). 8 Here, we investigated KIR genes as additional markers for early chimerism assessment after dUCBT. KIR gene content varies between individuals who can exhibit seven to fourteen inhibitory and activating KIR genes, defining multiple KIR genotypes.…”

“…Indeed, inhibitory KIR present high allelic polymorphism, such as KIR3DL1, which also affects KIR3DL1 expression. 8 The study of allele polyhaematologica 2015; 100:e475…”