The MICA‐129 dimorphism affects NKG2D signaling and outcome of hematopoietic stem cell transplantation

The MHC class I chain‐related molecule A (MICA) is a highly polymorphic ligand for the activating natural killer (NK)‐cell receptor NKG2D. A single nucleotide polymorphism causes a valine to methionine exchange at position 129. Presence of a MICA‐129Met allele in patients ( n = 452) undergoing hematopoietic stem cell transplantation (HSCT) increased the chance of overall survival (hazard ratio [HR] = 0.77, P = 0.0445) and reduced the risk to die due to acute graft‐versus‐host disease (aGVHD) (odds ratio [OR] = 0.57, P = 0.0400) although homozygous carriers had an increased risk to experience this complication (OR = 1.92, P = 0.0371). Overall survival of MICA‐129Val/Val genotype carriers was improved when treated with anti‐thymocyte globulin (HR = 0.54, P = 0.0166). Functionally, the MICA‐129Met isoform was characterized by stronger NKG2D signaling, triggering more NK‐cell cytotoxicity and interferon‐γ release, and faster co‐stimulation of CD8 + T cells. The MICA‐129Met variant also induced a faster and stronger down‐regulation of NKG2D on NK and CD8 + T cells than the MICA‐129Val isoform. The reduced cell surface expression of NKG2D in response to engagement by MICA‐129Met variants appeared to reduce the severity of aGVHD. Synopsis Allogeneic hematopoietic stem cell transplantation still has a high risk of post‐transplant complications including graft versus host disease and relapse of malignancy. Detection of single nucleotide polymorphisms may help to provide a risk‐adapted treatment. The MICA‐129Met/Val dimorphism was associated with an increased survival and a reduced risk to die due to acute graft versus host disease in a cohort of 452 patients. The survival of MICA‐129Val/Val genotype carriers was improved when treated with antithymocyte globulin (ATG). The MICA‐129Met isoform triggered more NK‐cell cytotoxicity and interferon‐γ release and it co‐stimulated cytotoxic T cells faster. The MICA‐129Met isoform also induced a faster and stronger down‐regulation of NKG2D on NK and cytotoxic T cells limiting the initially stronger functional effects. MICA‐129Val/Val carriers might profit from a T‐cell depleting treatment since this MICA variant has a lower ability to down‐regulate NKG2D and to limit the activation of alloreactive T cells. Graphical Abstract Allogeneic hematopoietic stem cell transplantation still has a high risk of post‐transplant complications including graft versus host disease and relapse of malignancy. Detection of single nucleotid