Liver transplantation (LT) offers a good survival chance for both the patient in short or long term, but still faces many challenges in the treatment of LT, such as the side effects associated with long-term immunosuppression, which is one of the side effects that occurs in most patients. However, the dynamics of the cellular immune system composition over time during immune tolerance to LT after immunosuppressive therapy are not known.Using single-cell transcriptome sequencing, we analyzed five peripheral blood samples (one normal individual and four patients who underwent LT and received immunosuppressive therapy for 2 months, 1 year, 3 years, and 7 years, respectively) for immune cell composition and gene expression.A total of 17,462 peripheral blood mononuclear cells were acquired from a normal individual without LT and patients who underwent LT and received immunosuppressive therapy for 2 months, 1 year, 3 years, and 7 years, respectively. A total of 24 cell clusters were obtained and categorized into four different cell types based on gene expression characteristics as follows: eight clusters of T cells, two clusters of B cells, two clusters of neutrophils, two clusters of monocytes, natural killer cells, and natural killer T (NKT) cells (n = 4), and six other cell clusters. Cell subset analysis, pseudotime analysis, and intercellular communication analysis revealed that the CD8+ NKT cells specifically expressed NKG2A (KLRC1, CD159A), which may be an important cell group for CD8+ NKG2A+ NKT cells in LT, thereby highlighting the heterogeneity and functional diversity in patients who undergo LT.We comprehensively analyzed single-cell RNA sequencing data from a normal individual and patients who underwent LT and elucidated the mechanism underlying the development of immune tolerance in LT. CD8+ NKT cells specifically expressing KLRC1 play a crucial role in LT, and dynamic monitoring of these cells may provide novel avenues for the diagnosis and treatment of LT-related immune rejection.© 2023 The Authors. Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.