Centromeric KIR AA Individuals Harbor Particular KIR Alleles Conferring Beneficial NK Cell Features with Implications in Haplo-Identical Hematopoietic Stem Cell Transplantation.

Léa Dubreuil,Catherine Willem,Bercelin Maniangou,Dhon Roméo Makanga,Nolwenn Legrand,Agnès Quéméner,Katia Gagne,Anne Cesbron,Marie C Béné,Christelle Retière,Mehdi Alizadeh,Patrice Chevallier,Ketevan Gendzekhadze,Gaëlle David

doi:10.3390/cancers12123595

Abstract

Simple SummaryWe have recently shown a broad disparity of Natural Killer (NK) cell responses against leukemia, highlighting good and bad responders resting on the Killer cell Immunoglobulin-like Receptors (KIR) and HLA genetics. In this study, we deeply investigated KIR2DL NK cell repertoire in combining high-resolution KIR allele typing and multicolor flow cytometry from a cohort of 108 blood donors. Our data suggest that centromeric (cen) AA individuals display more efficient KIR2DL alleles (L1*003 and L3*001) to mount a consistent frequency of KIR2DL+ NK cells and to confer an effective NK cell responsiveness. The transposition of our in vitro observations in T-replete haplo-identical Hematopoietic Stem Cell Transplantation (HSCT) context led us to observe that cenAA HSC grafts limit significantly the incidence of relapse in patients with myeloid diseases after T-replete haplo-identical HSCT. As NK cells are crucial in HSCT reconstitution, one could expect that the consideration of KIR2DL1/2/3 allelic polymorphism could help to refine scores used for HSC donor selection.We have recently shown a broad disparity of Natural Killer (NK) cell responses against leukemia highlighting good and bad responders resting on the Killer cell Immunoglobulin-like Receptors (KIR) and HLA genetics. In this study, we deeply studied KIR2D allele expression, HLA-C recognition and functional effect on NK cells in 108 blood donors in combining high-resolution KIR allele typing and multicolor flow cytometry. The KIR2DL1*003 allotype is associated with centromeric (cen) AA motif and confers the highest NK cell frequency, expression level and strength of KIR/HLA-C interactions compared to the KIR2DL1*002 and KIR2DL1*004 allotypes respectively associated with cenAB and BB motifs. KIR2DL2*001 and *003 allotypes negatively affect the frequency of KIR2DL1+ and KIR2DL3+ NK cells. Altogether, our data suggest that cenAA individuals display more efficient KIR2DL alleles (L1*003 and L3*001) to mount a consistent frequency of KIR2DL+ NK cells and to confer an effective NK cell responsiveness. The transposition of our in vitro observations in the T-replete haplo-identical HSCT context led us to observe that cenAA HSC grafts limit significantly the incidence of relapse in patients with myeloid diseases after T-replete haplo-identical HSCT. As NK cells are crucial in HSCT reconstitution, one could expect that the consideration of KIR2DL1/2/3 allelic polymorphism could help to refine scores used for HSC donor selection.

Highlights

IntroductionThey sense the absence of or decreased HLA class I expression on tumoral or virally infected cells and allogenic cells
Natural Killer (NK) cells are granular lymphocytes and form part of the innate immune system.They sense the absence of or decreased HLA class I expression on tumoral or virally infected cells and allogenic cells
We deeply investigated the influence of KIR2DL1/2/3 allelic polymorphism inhibitory rather than for the activating Killer cell Immunoglobulin-like Receptors (KIR) genes

Summary

Introduction

They sense the absence of or decreased HLA class I expression on tumoral or virally infected cells and allogenic cells They are important in Hematopoietic Stem Cell Transplantation (HSCT), being the first cytotoxic lymphocytes to appear during immune reconstitution before T cell recovery [1], and they are engaged in the beneficial Graft-versus Leukemia (GvL) effect [2,3]. This missing-self recognition by NK cells [4] is mediated through different receptors specific for HLA class I molecules [5]. The absence of inhibitory KIR engagement with its cognate ligand results in triggering KIR+ NK cell functions

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Discussion

Conclusion