Interleukin-21 promotes Type-1 activation and cytotoxicity of CD56^dimCD16^bright natural killer cells during kidney allograft antibody-mediated rejection showing a new link between adaptive and innate humoral allo-immunity.

Abstract

The role of Natural killer (NK) cells during kidney allograft antibody-mediated rejection (ABMR) is increasingly recognized, but an in-depth characterization of mechanisms that contribute to such immune response is still under investigation. Here, we characterized phenotypic, functional, and transcriptomic profiles of peripheral blood circulating and allograft infiltrating CD56^dimCD16^bright NK cells during anti-HLA donor-specific antibody (DSA)+ ABMR. Cross-sectional analyses performed in 71 kidney transplant recipients identified a unique phenotypic circulating CD56^dimCD16^bright NK cell cluster expanded in DSA+ ABMR. This cluster co-expressed high levels of the interleukin-21 Receptor (IL-21R); Type-1 transcription factors T-bet and EOMES, CD160 and natural killer group 2D cytotoxic and activating co-stimulatory receptors. CD160⁺ IL-21R⁺ NK cells correlated with elevated plasma IL-21, Ki-67⁺ ICOS⁺ (CD278) IL-21-producing circulating T follicular helper cells, enhanced Type-1 pro-inflammatory cytokines, NK cell cytotoxicity, worse microvascular inflammation and graft loss. Single-cell transcriptomic analysis of circulating NK cells delineated an expanded cluster in DSA+ ABMR characterized by elevated pro-inflammatory/cytotoxic pathways, IL-21/STAT3 signaling, and leukocyte trans-endothelial migration pathways. Infiltration of CD160⁺ IL-21R⁺ NK cells with similar transcriptomic profile was detected in DSA+ ABMR allograft biopsies, potentially contributing to allograft injury. Thus, the IL-21/IL-21R axis, linking adaptive and innate humoral allo-immunity, or NK cells may represent appealing immunotherapy targets in DSA+ ABMR.