CD8+ T Cell Differentiation Into NK-Like Effector Cells Drives Transplant Rejection

Authors

• Dawei Zou
• Stephanie G Yi
• Yulin Dai
• Luan Truong
• Lillian W Gaber
• Richard J Knight
• Xiang Xiao
• Rafik M Ghobrial
• Xian C Li
• Zhongming Zhao
• Wenhao Chen
• A Osama Gaber

Language

English

Publication Date

5-6-2026

Journal

Molecular Therapy

DOI

10.1016/j.ymthe.2026.01.024

PMID

41572631

PMCID

PMC12967240

PubMedCentral® Posted Date

6-19-2026

PubMedCentral® Full Text Version

Author MSS

Abstract

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)+ 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 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.

Keywords

CD8-Positive T-Lymphocytes, Animals, Graft Rejection, Cell Differentiation, Mice, Humans, Killer Cells, Natural, Interferon Regulatory Factors, Interferon Regulatory Factor-4, Kidney Transplantation, TOR Serine-Threonine Kinases, Gene Expression Profiling, Biomarkers, T cell, Transplant rejection, scRNA-seq, CD8+ T cell differentiation, IRF4, NK-like, Kidney transplantation, Costimulation blockade, Rapamycin

Published Open-Access

yes

Recommended Citation

Zou, Dawei; Yi, Stephanie G; Dai, Yulin; et al., "CD8+ T Cell Differentiation Into NK-Like Effector Cells Drives Transplant Rejection" (2026). Faculty, Staff and Student Publications. 1031.
https://digitalcommons.library.tmc.edu/uthshis_docs/1031