Abstract
Natural intraepithelial lymphocytes (IELs) are thymus-derived adaptive immune cells, which are important contributors to intestinal immune homeostasis. Similar to other innate-like T cells, they are induced in the thymus through high-avidity interaction that would otherwise lead to clonal deletion in conventional CD4 and CD8 T cells. By applying single-cell RNA-sequencing (scRNA-seq) on a heterogeneous population of thymic CD4-CD8αβ-TCRαβ+NK1.1- IEL precursors (NK1.1- IELPs), we define a developmental trajectory that can be tracked based on the sequential expression of CD122 and T-bet. Moreover, we identify the Id proteins Id2 and Id3 as a novel regulator of IELP development and show that all NK1.1- IELPs progress through a PD-1 stage that precedes the induction of T-bet. The transition from PD-1 to T-bet is regulated by the transcription factor C-Myc, which has far reaching effects on cell cycle, energy metabolism, and the translational machinery during IELP development. In summary, our results provide a high-resolution molecular framework for thymic IEL development of NK1.1- IELPs and deepen our understanding of this still elusive cell type.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, Ly / metabolism
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Cells, Cultured
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Gene Expression Regulation
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Immunity, Innate
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Inhibitor of Differentiation Protein 2 / genetics
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Inhibitor of Differentiation Protein 2 / metabolism
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Inhibitor of Differentiation Proteins / genetics
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Inhibitor of Differentiation Proteins / metabolism
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Interleukin-2 Receptor beta Subunit / genetics
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Interleukin-2 Receptor beta Subunit / metabolism
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Intraepithelial Lymphocytes / immunology*
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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NK Cell Lectin-Like Receptor Subfamily B / metabolism
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Precursor Cells, T-Lymphoid / immunology*
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Proto-Oncogene Proteins c-myc / metabolism*
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Sequence Analysis, RNA
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Single-Cell Analysis
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T-Box Domain Proteins / genetics
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T-Box Domain Proteins / metabolism*
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Thymus Gland / immunology*
Substances
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Antigens, Ly
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Idb2 protein, mouse
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Inhibitor of Differentiation Protein 2
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Inhibitor of Differentiation Proteins
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Interleukin-2 Receptor beta Subunit
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Klrb1c protein, mouse
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Myc protein, mouse
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NK Cell Lectin-Like Receptor Subfamily B
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Proto-Oncogene Proteins c-myc
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T-Box Domain Proteins
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T-box transcription factor TBX21
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Idb3 protein, mouse