The genotype of RAET1L (ULBP6), a ligand for human NKG2D (KLRK1), markedly influences the clinical outcome of allogeneic stem cell transplantation

Abstract

NKG2D (KLRK1) is an activating receptor on natural killer (NK) and T-cells and binds a diverse panel of polymorphic ligands encoded by the MIC and RAET1 gene families. We studied the clinical importance of retinoic acid early transcript-1 (RAET1) polymorphism in allogeneic stem cell transplantation (SCT) by determining the frequency of 18 single nucleotide polymorphisms (SNPs) and individual RAET1 alleles in 371 patient-donor pairs and relating this to clinical outcome. A strong association was observed between the presence of five SNPs within the patient RAET1L (ULBP6) gene and relapse-free survival and overall survival. Two common alleles of RAET1L were determined and the presence of the protective RAET1L*02 allele in the patient was associated with a relapse-free survival of 44% at 8 years compared with just 25% in patients who lacked a RAET1L*02 allele (P < 0·001). Overall survival at this time was 55% in those with RAET1L*02 allele compared to 39% in patients who lacked a RAET1L*02 allele (P = 0·003). These novel findings indicate a critical role for NKG2D-RAET1L interactions in determining SCT clinical outcome and show RAET1L may have an important influence on regulating the strength of the alloreactive immune response. The data will be of value in guiding the development of future transplant therapy protocols.