Clinical findings suggest a role for donor MHC class I-related chain A (MICA) antigens expressed on transplant endothelial cells (ECs) in the alloimmune response. However, MICA genotyping is not routinely achieved and molecular bases for MICA allospecific immunization are still unclear. This study investigated the immunological impact of the A5.1 mutation, related to the most common MICA*008 allele, in kidney transplantation from cellular to clinical levels. Firstly, we show that in our cohort of transplant donors, 13.1% of transplant donors were homozygous for MICA A5.1 mutation while 46.4% were heterozygous. Using primary endothelial cell cultures isolated from transplant donors at the time of transplantation (WT/WT; WT/A5.1 and A5.1/A5.1, at least n=4 for each group) we demonstrate that MICA surface expression was dramatically higher (7-10-fold increase) on ECs from MICA A5.1/A5.1 donors compared to the controls. Associated with an enhanced MICA expression, A5.1 mutation also correlates with the exclusive production of circulating MICA molecules in exosomes, expressing high level of MICA, and a lack of shedded soluble forms. Mechanistically, we demonstrate that elevated MICA expression on ECs correlates with high transcript level but was not due to change in protein stability, expression of regulatory miRNAs (miR-20a; -105; -106b; -373; -520b; -520f; -636). Sequencing reveals no MICA A5.1-specific SNPs in 3’UTR or 5’UTR regions. Clinically, we demonstrated that polyreactive anti-MICA transplant recipient’s sera bind preferentially to MICA A5.1 donor ECs supporting a key role for MICA*008/A5.1 molecules as both major antigenic determinants and targets on graft’s ECs. By determining the incidence of MICA A5.1 mismatch, in a retrospective cohort study, we provide the first evidence for a statistically significant association between MICA A5.1 on transplant donor and both anti-MICA sensitization (frequency and strength) and increased proteinuria in kidney recipients. Together, our findings identify the MICA A5.1 mutation as an immunodominant factor and a potential risk factor for transplant survival.

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