Single-cell analysis reveals the origins and intrahepatic development of liver-resident IFN-γ-producing γδ T cells

gamma delta T cells are heterogeneous lymphocytes located in various tissues. However, a systematic and comprehensive understanding of the origins of gamma delta T cell heterogeneity and the extrathymic developmental pathway associated with liver gamma delta T cells remain largely unsolved. In this study, we performed single-cell RNA sequencing (scRNA-seq) to comprehensively catalog the heterogeneity of gamma delta T cells derived from murine liver and thymus samples. We revealed the developmental trajectory of gamma delta T cells and found that the liver contains gamma delta T cell precursors (pre-gamma delta T cells). The developmental potential of hepatic gamma delta T precursor cells was confirmed through in vitro coculture experiments and in vivo adoptive transfer experiments. The adoptive transfer of hematopoietic progenitor Lin(-)Sca-1(+)Mac-1(+) (LSM) cells from fetal or adult liver samples to sublethally irradiated recipients resulted in the differentiation of liver LSM cells into pre-gamma delta T cells and interferon-gamma(+) (IFN-gamma(+)) but not interleukin-17a(+) (IL-17a(+)) gamma delta T cells in the liver. Importantly, thymectomized mouse models showed that IFN-gamma-producing gamma delta T cells could originate from liver LSM cells in a thymus-independent manner. These results suggested that liver hematopoietic progenitor LSM cells were able to differentiate into pre-gamma delta T cells and functionally mature gamma delta T cells, which implied that these cells are involved in a distinct developmental pathway independent of thymus-derived gamma delta T cells.

Automated summary

In this study, the heterogeneity of gamma delta T cells from murine liver and thymus samples was comprehensively cataloged using single-cell RNA sequencing. It was revealed that liver contains gamma delta T cell precursors, which can differentiate into functionally mature gamma delta T cells independent of the thymus-derived pathway. These findings highlight a distinct developmental pathway for gamma delta T cells in the liver.