Alloreactive adaptive Natural Killer cells in renal transplantation: potential contribution to allograft microvascular inflammation.

Inhibitory Killer-cell immunoglobulin-like receptors (iKIR) are randomly expressed by Natural Killer (NK) cell subsets and recognize motifs shared by HLA class-I allotypes. Such interactions prevent NK cell autoreactivity while enhancing their response against cells lacking those HLA-I molecules (missing self), a situation defined in transplantation as iKIR-HLA-I mismatch (iKIR-MM), whose genotypic prediction has been associated with microvascular inflammation (MVI). Herein we compared iKIR-MM in kidney transplant recipients (KTR) with MVI≥2 (n=19) and controls with MVI≤1 (n=36). In parallel to genetic analysis of iKIR-MM, which was more frequent in MVI≥2 patients, putative alloreactive iKIR-MM NK cells were defined by flow cytometry as NKG2A(-) cells bearing self-specific but lacking donor-specific iKIR. Although iKIR-MM NK cells were detected in both groups, their pretransplant numbers were higher in MVI≥2 patients (median=11.02, IQR=0-58.31 vs median=0, IQR=0-9.46), especially in the presence of DSA or C4d and correlated with MVI grade. A subset of MVI≥2 patients showed pretransplant high proportions and numbers of oligoclonal iKIR-MM NK cells, which displayed an NKG2C(+) adaptive phenotype associated with cytomegalovirus infection. This pilot study provides a novel perspective on the contribution of iKIR-MM NK cells to MVI, with potential practical implications.