Non-Expressed Donor KIR3DL1 Alleles May Represent a Risk Factor for Relapse after T-Replete Haploidentical Hematopoietic Stem Cell Transplantation
LEGRAND N. 1,2,6, SALAMEH P. 1,2,6, JULLIEN M. 1,2,3,6, CHEVALLIER P. 1,3, FERRON E. 1,2,6, DAVID G. 1,2,6, DEVILDER M. 1,6, WILLEM C. 1,2,6, GENDZEKHADZE K. 4, PARHAM P. 5, RETIÈRE C. 1,2,6, GAGNE K. 1,2,6
1 CRCI2NA, INSERM UMR1307, CNRS UMR6075, Nantes, France; 2 Etablissement Français du Sang (EFS), Nantes, France; 3 Department of Hematology Clinic, Nantes University Hospital, Nantes, France; 4 Department of Hematology and HCT, HLA laboratory, Duarte, United States; 5 Department of Structural Biology and Microbiology & Immunology, Stanford, United States; 6 LabEx IGO “Immunotherapy, Graft, Oncology, Nantes, France; 7 LabEx Transplantex, Strasbourg, France
KIR3DL1 alleles are expressed at different levels on the natural killer (NK) cell surface. In particular, the non-expressed KIR3DL1*004 allele appears to be common in Caucasian populations. However, the overall distribution of non-expressed KIR3DL1 alleles and their clinical relevance after T-replete haploidentical hematopoietic stem cell transplantation (hHSCT) with post-transplant cyclophosphamide remain poorly documented in European populations. In a cohort of French blood donors (N = 278), we compared the distribution of expressed and non-expressed KIR3DL1 alleles using next-generation sequencing (NGS) technology combined with multi-color flow cytometry. We confirmed the predominance of the non-expressed KIR3DL1*004 allele. Using allele-specific constructs, the phenotype and function of the uncommon KIR3DL1*019 allotype were characterized using the Jurkat T cell line and NKL transfectants. Although poorly expressed on the NK cell surface, KIR3DL1*019 is retained within NK cells, where it induces missing self-recognition of the Bw4 epitope. Transposing our in vitro observations to a cohort of hHSCT patients (N = 186) led us to observe that non-expressed KIR3DL1 HSC grafts increased the incidence of relapse in patients with myeloid diseases. Non-expressed KIR3DL1 alleles could therefore, influence the outcome of hHSCT.