Data are shown as medians and interquartile range (IQR) or n and the percentage. P values were computed using χ² tests for categorical variables or two-sided Kruskal-Wallis tests for continuous variables. CD4, CD4 T cells; CD8, CD8 T cells; WBCs, white blood cells. a P value on clinical grade was based on comparison among symptomatic S2, S3 and convalescent S4 patients excluding S1. Clinical grade classification was infeasible for presymtomatic S1 patients who did not exhibit any clinical symptoms at the time of blood collection.

ObjectiveA comprehensive immune landscape for HBV infection is pivotal to achieve HBV cure.DesignWe performed single-cell RNA sequencing of 2 43 000 cells from 46 paired liver and blood samples of 23 individuals, including six immune tolerant, 5 immune active (IA), 3 acute recovery (AR), 3 chronic resolved and 6 HBV-free healthy controls (HCs). Flow cytometry and histological assays were applied in a second HBV cohort for validation.ResultsBoth IA and AR were characterised by high levels of intrahepatic exhausted CD8+ T (Tex) cells. In IA, Tex cells were mainly derived from liver-resident GZMK+ effector memory T cells and self-expansion. By contrast, peripheral CX3CR1+ effector T cells and GZMK+ effector memory T cells were the main source of Tex cells in AR. In IA but not AR, significant cell–cell interactions were observed between Tex cells and regulatory CD4+ T cells, as well as between Tex and FCGR3A+ macrophages. Such interactions were potentially mediated through human leukocyte antigen class I molecules together with their receptors CANX and LILRBs, respectively, contributing to the dysfunction of antiviral immune responses. By contrast, CX3CR1+GNLY+ central memory CD8+ T cells were concurrently expanded in both liver and blood of AR, providing a potential surrogate marker for viral resolution. In clinic, intrahepatic Tex cells were positively correlated with serum alanine aminotransferase levels and histological grading scores.ConclusionOur study dissects the coordinated immune responses for different HBV infection phases and provides a rich resource for fully understanding immunopathogenesis and developing effective therapeutic strategies.

No abstract

No abstract