Homo sapiens Raw sequence reads. Homo sapiens

Immune tolerance after transplantation reduces immunosuppression related complications and improves the overall survival rates. The unique tolerogenic microenvironment of liver enables a proportion of liver transplantation (LT) recipients to develop tolerance with intact liver function. However, the underlying immunological mechanisms remain unclear. Here we show that Epstein-Barr virus (EBV) provides the surrogate peptide to prime KIR+ CX3CR1+ CD8+ T cells and induce immune tolerance after LT. In the pediatric LT clinical cohort, we found that the ratio of KIR+ CX3CR1+ CD8+ T cells is significantly higher in tolerant recipients. As part of CD8+ TEMRA, these KIR+ CX3CR1+ CD8+ T cells exhibit features of terminal differentiation and cytotoxicity, employing perforin and granzyme B to eradicate alloreactive CD4+ T cells. In vitro analysis unveiled that a peptide, SQAPLPCVL, derived from EBV could stabilize the HLA-E expression on alloreactive CD4+ T cells and mediate the recognition and elimination by KIR+ CX3CR1+ CD8+ T cells. Furthermore, BATF, a basic leucine zipper transcriptional factor, is found as indispensable for the induction of KIR+ CX3CR1+ CD8+ T cells as deletion of BATF in T cells abolished the transition toward Ly49+ (homolog of KIR in mice) CD8+ T cells under IL-15 and IL-21 treatment. A prospective immunosuppressant withdrawal clinical trial in pediatric LT recipients confirmed that peripheral ratio of CD8+ TEMRA cells can serve as a reliable predictive biomarker to identify tolerant recipients during long-term follow-up. Taken together, our study demonstrated a new immune tolerance mechanism mediated by KIR+ CD8+ T cells and established the connection between viral infection and tolerance formation, providing new insights into the tolerance inductive strategies after transplantation.

移植术后免疫耐受可降低免疫抑制相关并发症发生率，并提升总体生存率。肝脏独特的致耐受微环境，使得部分肝移植（liver transplantation, LT）受者可在肝功能完好的状态下产生免疫耐受。然而，其潜在的免疫学机制仍未阐明。本研究发现，爱泼斯坦-巴尔病毒（Epstein-Barr virus, EBV）可通过提供替代肽致敏KIR+ CX3CR1+ CD8+ T细胞，从而诱导肝移植术后免疫耐受。在儿科肝移植临床队列中，我们观察到免疫耐受受者体内的KIR+ CX3CR1+ CD8+ T细胞比例显著升高。作为CD8+ TEMRA细胞的亚群之一，这类KIR+ CX3CR1+ CD8+ T细胞具备终末分化与细胞毒性特征，可通过穿孔素与颗粒酶B清除同种反应性CD4+ T细胞。体外实验分析显示，源自EBV的肽段SQAPLPCVL可稳定同种反应性CD4+ T细胞表面的HLA-E表达，并介导KIR+ CX3CR1+ CD8+ T细胞对其的识别与清除。进一步研究表明，碱性亮氨酸拉链转录因子BATF是诱导KIR+ CX3CR1+ CD8+ T细胞生成的关键调控因子：当T细胞中BATF基因缺失时，IL-15与IL-21处理下细胞向Ly49+（小鼠KIR同源物）CD8+ T细胞的转化过程会被完全阻断。一项针对儿科肝移植受者的前瞻性免疫抑制剂撤除临床试验证实，外周血CD8+ TEMRA细胞比例可作为可靠的预测生物标志物，在长期随访中精准识别免疫耐受受者。综上，本研究揭示了一种由KIR+ CD8+ T细胞介导的新型免疫耐受机制，建立了病毒感染与耐受形成之间的潜在关联，为移植术后耐受诱导策略提供了全新的研究视角。