Single-cell RNA-seq of mouse thymus iNKT cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE130184 | GEO | 2022/08/10
REPOSITORIES: GEO
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Project description:Invariant natural killer T (iNKT) cells are a specific innate-like counterpart of T lymphocytes, which response to lipid-based antigens and provide a functional bridge between the innate and adaptive immunity. The physiological role of m6A modification involved in NK cells differentiation remains unclear. We found that N6-Methyladenosine (m6A) methyltransferase METTL3 is intrinsically required for iNKT cell development and function in an m6A-dependent manner. To investigate the molecular mechanisms, m6A-LACE-seq was performed using iNKT cells and Merip-seq was performed using DP cells in thymocytes isolated from WT and KO mice to investigate the regulatory network.
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Project description:Invariant natural killer T cells (iNKT) cells are differently distributed in various immune organs. However, it remains unclear whether iNKT cells exhibit phenotypical and functional differences in different peripheral organs and how thymic iNKT migrate to peripheral organs. Hence, characterizing iNKT cells in peripheral organs is important.
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Project description:Invariant Natural Killer T (iNKT) cells are a unique subset of T lymphocytes with a memory like phenotype which express invariant T cell receptor (TCR) chain comprised of a Vα14-Jα18 rearrangement in mice. In the present study, we characterize the transcriptomes of thymic iNKT cells at the single cell level to reveal the underlying metabolic adaptation that exists over the course of iNKT cell development.
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Project description:Invariant natural killer T (iNKT) cells are a specific innate-like counterpart of T lymphocytes, which response to lipid-based antigens and provide a functional bridge between the innate and adaptive immunity. The physiological role of m6A modification involved in NK cells differentiation remains unclear. We found that N6-Methyladenosine (m6A) methyltransferase METTL3 is intrinsically required for iNKT cell development and function in an m6A-dependent manner. To investigate the molecular mechanisms, RNA-seq was performed using iNKT cells in thymocytes isolated from WT and KO mice to investigate the regulatory network.
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Project description:T cell development is a complicatedly hierarchical process which is closely related with the chromatin activation and gene transcription. CD4+CD8+ double-positive (DP) thymocytes give rise to both conventional TCRαβ+ T cells and natural killer T cells, but they display different characteristics. Compared with conventional TCRαβ+ T cells, invariant natural killer T cells (iNKT cells) as the major population of NKT cells, are CD1d-restricted, recognize glycolipid antigens and rapidly exert effector functions after stimulation. However, the specific molecular mechanism of early iNKT cell development remain incompletely understood. Here the authors show that deletion of Chromatin assembly factor 1B (CHAF1b) remains the normal development of conventional TCRαβ+ T cell, but specifically impacts iNKT cell generation and completely impairs iNKT cell development from stage 0 with a PLZF independent way. This dysregulation is accompanied by a specific decrease in gene transcription of Vα14-Jα18, an impairment in TCR signaling and PLZF expression. Notably, ectopic expression of a transgenic Vα14-Jα18 TCR completely rescues these defects in Chaf1b-deficient iNKT cells. Moreover, cytokine secretion and anti-tumor activity are substantially maintained in Chaf1b-deficient iNKT cells with transgenic Vα14-Jα18 TCR. Our study identifies CHAF1b as a distinct regulator controls early development of iNKT cells via transcriptional regulation of Vα14-Jα18.
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Project description:The maintenance of tissue homeostasis is critically dependent on the function of tissue-resident lymphocytes, including lipid-reactive invariant natural killer T (iNKT) cells. iNKT cells have unique properties according to their tissues of residency, but if and how the tissue environment shapes their antigen specificity remains unknown. By analysing iNKT cells from tissues of mice and humans we demonstrate that their T cell receptor (TCR) repertoire is highly diverse and is distinct for iNKT cells resident in individual tissues resulting in differential lipid-antigen recognition. Within peripheral tissues, the TCR repertoire of iNKT cell recent thymic emigrants is different from that of mature cells, indicating that the iNKT population is shaped after their arrival to the tissues. Accordingly, in homeostatic conditions the repertoire of iNKT cells is modulated by tissue-specific signals that control iNKT cell activation and proliferation resulting in differential clonal expansion found for cells resident in various organs. Moreover, the iNKT cell TCR repertoire changes in response to lipid immunization and is shaped by age and by environmental changes. Thus, post-thymic modification of the iNKT cell TCR repertoire underpins the distinct antigen specificity of iNKT cells residing in peripheral tissues
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Project description:Invariant natural killer T cells (iNKT) expressing the retinoic acid receptor-related orphan receptor γt (RORγt) and producing IL-17 represent a minor subset of CD1d-restricted iNKT cells (iNKT17) in C57BL/6J (B6) mice. We aimed in this study to define the reasons for their low distribution and the sequence of events accompanying their normal thymic development. We found that RORγt+ iNKT cells have higher proliferation potential and a greater propensity to apoptosis than RORγt- iNKT cells. These cells do not likely reside in the thymus indicating that thymus emigration, and higher apoptosis potential, could contribute to RORγt+ iNKT cell reduced thymic distribution. Ontogeny studies suggest that mature HSAlow RORγt+ iNKT cells might develop through developmental stages defined by a differential expression of CCR6 and CD138 during which RORγt expression and IL-17 production capabilities are progressively acquired. Finally, we found that RORγt+ iNKT cells perceive a strong TCR signal that could contribute to their entry into a specific Th17 like developmental program influencing their survival and migration. Overall, our study proposes a hypothetical thymic developmental sequence for iNKT17 cells, which could be of great use to study molecular mechanisms regulating this developmental program.
2019-10-19 | GSE139084 | GEO
Project description:iNKT cells are highly conserved innate-like T lymphocytes that develop from CD4+CD8+ DP cells. It remains largely unknown whether post-transcriptional regulation has critical roles in iNKT cells. Here we show conditional deactivation of SRSF1 in DP thymocytes impaired iNKT cell development and survival in a cell-intrinsic manner.
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