Journal of hepatology · 2026
EBV-reactive KIR+ CX3CR1+ CD8+ T cells mediate liver transplantation tolerance.
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Liu Yongbo, Wang Bingran, Sun Di, Zhou Aiwei, Cai Zimeng, Zhou Tao, Yang Sen, Pan Qi, Gao Yunmu, Song Jiaqi, Zong Zhipeng, Xiao Wanglong, Liu Hongyuan, Yang Taihua, Zhao Zhicong, Luo Yi, Zhang Jianjun, Fang Jianchen, Zhan Zhenzhen, Lu Linrong, Liu Yuan, Xia Qiang
Аннотация
BACKGROUND & AIMS: Immune tolerance after transplantation reduces immunosuppression-related complications and improves the overall survival rates. The unique tolerogenic microenvironment of the liver enables a proportion of liver transplantation (LT) recipients to develop tolerance with intact liver function. However, the underlying immunological mechanisms remain unclear.
METHOD: s: We integrated single-cell transcriptome/TCR profiling, flow cytometry, in vitro killing assays, HLA-E peptidome from a retrospective cohort including 347 LT recipients, murine LT models, and a 20-participant prospective immunosuppressant withdrawal trial in pediatric LT recipients with median 26 months follow-up.
RESULTS: We demonstrated that Epstein-Barr virus (EBV)-derived peptides can be presented by HLA-E on alloreactive CD4+ T cells to prime KIR+ CX3CR1+ CD8+ T cells, thereby promoting immune tolerance after LT. As a subset of CD8+ TEMRA cells, KIR+ CX3CR1+ CD8+ T cells utilize perforin and granzyme B to suppress alloreactive CD4+ T cells after LT. In vitro analysis unveiled that the EBV-derived peptide SQAPLPCVL could stabilize HLA-E expression on alloreactive CD4+ T cells and mediate recognition and elimination by KIR+ CX3CR1+ CD8+ T cells through a TCR-dependent mechanism. Furthermore, BATF was indispensable for induction of KIR+ CX3CR1+ CD8+ T cells. In the prospective immunosuppressant withdrawal clinical trial, the peripheral ratio of CD8+ TEMRA and KIR+ CX3CR1+ CD8+ T cells were suggested to be potentially useful in identifying tolerant recipients.
CONCLUSIONS: Our study demonstrated a new immune tolerance mechanism mediated by KIR+ CX3CR1+ CD8+ T cells and established the connection between viral infection and tolerance formation, providing new insights into tolerance-inductive strategies after transplantation.
METHOD: s: We integrated single-cell transcriptome/TCR profiling, flow cytometry, in vitro killing assays, HLA-E peptidome from a retrospective cohort including 347 LT recipients, murine LT models, and a 20-participant prospective immunosuppressant withdrawal trial in pediatric LT recipients with median 26 months follow-up.
RESULTS: We demonstrated that Epstein-Barr virus (EBV)-derived peptides can be presented by HLA-E on alloreactive CD4+ T cells to prime KIR+ CX3CR1+ CD8+ T cells, thereby promoting immune tolerance after LT. As a subset of CD8+ TEMRA cells, KIR+ CX3CR1+ CD8+ T cells utilize perforin and granzyme B to suppress alloreactive CD4+ T cells after LT. In vitro analysis unveiled that the EBV-derived peptide SQAPLPCVL could stabilize HLA-E expression on alloreactive CD4+ T cells and mediate recognition and elimination by KIR+ CX3CR1+ CD8+ T cells through a TCR-dependent mechanism. Furthermore, BATF was indispensable for induction of KIR+ CX3CR1+ CD8+ T cells. In the prospective immunosuppressant withdrawal clinical trial, the peripheral ratio of CD8+ TEMRA and KIR+ CX3CR1+ CD8+ T cells were suggested to be potentially useful in identifying tolerant recipients.
CONCLUSIONS: Our study demonstrated a new immune tolerance mechanism mediated by KIR+ CX3CR1+ CD8+ T cells and established the connection between viral infection and tolerance formation, providing new insights into tolerance-inductive strategies after transplantation.