Alloreactive adaptive natural killer cells in renal transplantation: potential contribution to allograft microvascular inflammation

Alari-Pahissa, Elisenda; Federico-Vega, Judith; Ataya Fernández, Michelle, 1993-; Buxeda, Anna; Bello-Rico, Víctor; Gimeno, Javier; Yélamos López, José; Altadill, Mireia; Sanz-Ureña, Sara; Riera, Marta; Burballa Tàrrega, Carla, 1988-; Chamoun, Betty Odette; Pérez-Sáez, María José; Redondo Pachón, María Dolores; Vilches, Carlos; Crespo Barrio, Marta; López-Botet, M. (Miguel)

doi:http://dx.doi.org/10.1016/j.ajt.2025.04.024

Alloreactive adaptive natural killer cells in renal transplantation: potential contribution to allograft microvascular inflammation

Citation

Alari-Pahissa E, Federico-Vega J, Ataya M, Buxeda A, Bello-Rico V, Gimeno J, et al. Alloreactive adaptive natural killer cells in renal transplantation: potential contribution to allograft microvascular inflammation. Am J Transplant. 2025 Aug;25(8):1657-69. DOI: 10.1016/j.ajt.2025.04.024

Abstract

Inhibitory killer cell immunoglobulin-like receptors (iKIRs) are randomly expressed by natural killer (NK) cell subsets and recognize motifs shared by HLA class-I (HLA-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 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, interquartile range = 0-58.31 vs median = 0, interquartile range = 0-9.46), especially in the presence of donor-specific antibodies or C4d, and correlated with MVI grade. Pretransplant, a subset of MVI ≥2 patients showed 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.