Abstract
γδ T cells with distinct properties develop in the embryonic and adult thymus and have been identified as critical players in a broad range of infections, antitumor surveillance, autoimmune diseases, and tissue homeostasis. Despite their potential value for immunotherapy, differentiation of γδ T cells in the thymus is incompletely understood. Here, we establish a high‐resolution map of γδ T‐cell differentiation from the fetal and adult thymus using single‐cell RNA sequencing. We reveal novel sub‐types of immature and mature γδ T cells and identify an unpolarized thymic population which is expanded in the blood and lymph nodes. Our detailed comparative analysis reveals remarkable similarities between the gene networks active during fetal and adult γδ T‐cell differentiation. By performing a combined single‐cell analysis of Sox13, Maf, and Rorc knockout mice, we demonstrate sequential activation of these factors during IL‐17‐producing γδ T‐cell (γδT17) differentiation. These findings substantially expand our understanding of γδ T‐cell ontogeny in fetal and adult life. Our experimental and computational strategy provides a blueprint for comparing immune cell differentiation across developmental stages.
Highlights
Advances in single-cell technologies have enabled an unbiased classification of immune cell types and the inference of their differentiation trajectories on a genome-wide scale
This lineage represents a unique developmental paradigm in immune cell ontogeny blurring the demarcation of the innate and adaptive arms of immunity (Lanier, 2013). cd T cells exert innate-like rapid immune responses by recognizing a broad spectrum of molecules including non-peptide antigens through T-cell receptor (TCR)-dependent and TCR-independent mechanisms (Hayday, 2009)
They are the earliest T cells to develop in the embryonic thymus, and their differentiation and effector functions are developmentally pre-programmed: Rearrangement of defined T-cell receptor (TCR) c chains occurs at discrete time points and is followed by selective migration to individual epithelial tissues such as skin, lung, intestine, and reproductive tract. cd T-cell development continues after birth in the thymus albeit utilizing different TCR c chains (Carding & Egan, 2002), and the naıve cells are believed to mature in the secondary lymphoid organs (Chien et al, 2013)
Summary
Advances in single-cell technologies have enabled an unbiased classification of immune cell types and the inference of their differentiation trajectories on a genome-wide scale. While a significant amount of research has focused on understanding the development of ab T cells, the cd lineage remains understudied This lineage represents a unique developmental paradigm in immune cell ontogeny blurring the demarcation of the innate and adaptive arms of immunity (Lanier, 2013). Cd T cells exert innate-like rapid immune responses by recognizing a broad spectrum of molecules including non-peptide antigens through TCR-dependent and TCR-independent mechanisms (Hayday, 2009) They are the earliest T cells to develop in the embryonic thymus, and their differentiation and effector functions are developmentally pre-programmed: Rearrangement of defined T-cell receptor (TCR) c chains occurs at discrete time points and is followed by selective migration to individual epithelial tissues such as skin, lung, intestine, and reproductive tract. They are the earliest T cells to develop in the embryonic thymus, and their differentiation and effector functions are developmentally pre-programmed: Rearrangement of defined T-cell receptor (TCR) c chains occurs at discrete time points and is followed by selective migration to individual epithelial tissues such as skin, lung, intestine, and reproductive tract. cd T-cell development continues after birth in the thymus albeit utilizing different TCR c chains (Carding & Egan, 2002), and the naıve cells are believed to mature in the secondary lymphoid organs (Chien et al, 2013)
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