CD8⁺ T cell differentiation into NK-like effector cells drives transplant rejection

T cells are central drivers of transplant rejection, yet the differentiation fates underlying this process remain unclear. Using single-cell transcriptomic profiling of human kidney allograft biopsies, we identified a predominant infiltrating CD8⁺ T cell subset exhibiting killer cell lectin-like receptor (KLR)⁺ natural killer (NK)-like features. Mechanistic studies in mice showed that the KLR⁺ subset emerged de novo post transplantation and dominated the CD8⁺ T cell infiltrate in rejecting allografts. These NK-like CD8⁺ T cells expressed high levels of interferon regulatory factor 4 (IRF4), and Irf4 deletion disrupted their differentiation and induced transplant acceptance. Therapeutically, either costimulation blockade or mammalian target of rapamycin (mTOR) inhibition substantially reduced the generation of NK-like CD8⁺ T cells; however, the persistence of these cells ultimately led to rejection. Notably, combining costimulation blockade with mTOR inhibition completely abrogated their generation and enabled transplant acceptance. Together, these findings identify KLR⁺ NK-like CD8⁺ T cells as key mediators of transplant rejection, highlighting the need for more effective strategies to block their differentiation and improve transplant outcomes.