EBV-reactive KIR+ CX3CR1+ CD8+ T cells mediate liver transplantation tolerance

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.

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.

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⁺ T_EMRA 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⁺ T_EMRA and KIR⁺ CX3CR1⁺ CD8⁺ T cells were suggested to be potentially useful in identifying tolerant recipients.

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.