Abstract
γδ T cells are heterogeneous lymphocytes located in various tissues. However, a systematic and comprehensive understanding of the origins of γδ T cell heterogeneity and the extrathymic developmental pathway associated with liver γδ T cells remain largely unsolved. In this study, we performed single-cell RNA sequencing (scRNA-seq) to comprehensively catalog the heterogeneity of γδ T cells derived from murine liver and thymus samples. We revealed the developmental trajectory of γδ T cells and found that the liver contains γδ T cell precursors (pre-γδ T cells). The developmental potential of hepatic γδ 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-γδ T cells and interferon-gamma+ (IFN-γ+) but not interleukin-17a+ (IL-17a+) γδ T cells in the liver. Importantly, thymectomized mouse models showed that IFN-γ-producing γδ 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-γδ T cells and functionally mature γδ T cells, which implied that these cells are involved in a distinct developmental pathway independent of thymus-derived γδ T cells.
Highlights
Origins and developmental pathways associated with γδ T cells based on single-cell analysis We first sorted thymic and hepatic γδ T cells using flow cytometry and investigated the profiles and heterogeneity associated with γδ T cells derived from murine thymus and liver samples using 10× Genomics scRNA-seq.[19]
According to the tissue distributions of the 8 clusters, we divided them into three classifications: cluster 1 (C1) and C2 were uniquely localized to the thymus and named C1-T and C2-T; C4, C5, C7, and C8 were uniquely localized to the liver and named C4-L, C5-L, C7-L, and C8-L; C3 and C6 were identified in both the thymus and liver and named C3-T/L and C6-T/L (Fig. 1a)
DISCUSSION γδ T cells are commonly believed to develop in the thymus, where CD4−CD8− double-negative cells that receive strong TCR signaling predominantly develop into γδ T cells.[28]
Summary
INTRODUCTION γδT cells are a unique group of lymphocytes that display immunologic features that are common to both the innate and adaptive immune systems. γδ T cells predominantly reside in mucosal and epithelial barriers and other peripheral tissues and respond rapidly during infection by exerting potent cytotoxic effects and producing cytokines, functioning as the first line of immune defense against infections.[1,2,3] γδ T cells regulate the activation, migration, and effector functions of other immune cells by producing cytokines and chemokines. γδ T cells play crucial roles in antitumor immune responses, exerting direct cytotoxic effects to eliminate tumor cells or indirectly modulating the activities and functions of other immune cells.[4,5] The functional plasticity of γδ T cells depends on the developmental program in the thymus and functional polarization in the periphery and correlates with γδ T cell subpopulations found in various tissue locations.[6]. Γδ T cells play crucial roles in antitumor immune responses, exerting direct cytotoxic effects to eliminate tumor cells or indirectly modulating the activities and functions of other immune cells.[4,5] The functional plasticity of γδ T cells depends on the developmental program in the thymus and functional polarization in the periphery and correlates with γδ T cell subpopulations found in various tissue locations.[6] Several γδ T cell subsets establish preferential residency in particular tissues.[7,8]. A growing body of evidence has indicated that some γδ T cells conserve plasticity and can differentiate into functional subpopulations in the periphery.[6,9] Extrathymic developmental programs appear to exist for γδ T cells, intestinal intraepithelial γδ (γδ IEL) T cells, which can develop locally in gut cryptopatches.[10] The adult liver contains hematopoietic stem and progenitor cells (HSPCs) and is considered to serve as an extramedullary hematopoietic organ. More recent studies have focused on the developmental origins of γδ T cells and related transcriptional programs.[13,14] the precise developmental program, the origins and extrathymic developmental pathways associated with liver γδ T cells, remains largely unsolved
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