Thymic Epithelial Cell-Derived IL-15 and IL-15 Receptor α Chain Foster Local Environment for Type 1 Innate Like T Cell Development

Tao, Huishan; Li, Lei; Liao, Nan‐Shih; Schluns, Kimberly S.; Luckhart, Shirley; Sleasman, John W.; Zhong, Xiao‐Ping

doi:10.3389/fimmu.2021.623280

Cited by 9 publications

(3 citation statements)

References 75 publications

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“…In addition, besides iNKT cells, we also found that γδT1 cells, which are a small population of thymocytes, were modestly decreased in FoxN1-Cre IL-15 cKO mice (fig. S3, D and E), consistent with a recent report ( 22 ). To exclude any influence from γδT1 cells, we analyzed FoxN1-Cre IL-15 cKO × TCRδ KO mice.…”

Section: Resultssupporting

confidence: 92%

A circulating subset of iNKT cells mediates antitumor and antiviral immunity

et al. 2022

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Invariant natural killer T (iNKT) cells are a group of innate-like T lymphocytes that recognize lipid antigens. They are supposed to be tissue resident and important for systemic and local immune regulation. To investigate the heterogeneity of iNKT cells, we recharacterized iNKT cells in the thymus and peripheral tissues. iNKT cells in the thymus were divided into three subpopulations by the expression of the natural killer cell receptor CD244 and the chemokine receptor CXCR6 and designated as C0 (CD244 − CXCR6 − ), C1 (CD244 − CXCR6 + ), or C2 (CD244 + CXCR6 + ) iNKT cells. The development and maturation of C2 iNKT cells from C0 iNKT cells strictly depended on IL-15 produced by thymic epithelial cells. C2 iNKT cells expressed high levels of IFN-γ and granzymes and exhibited more NK cell–like features, whereas C1 iNKT cells showed more T cell–like characteristics. C2 iNKT cells were influenced by the microbiome and aging and suppressed the expression of the autoimmune regulator AIRE in the thymus. In peripheral tissues, C2 iNKT cells were circulating that were distinct from conventional tissue-resident C1 iNKT cells. Functionally, C2 iNKT cells protected mice from the tumor metastasis of melanoma cells by enhancing antitumor immunity and promoted antiviral immune responses against influenza virus infection. Furthermore, we identified human CD244 + CXCR6 + iNKT cells with high cytotoxic properties as a counterpart of mouse C2 iNKT cells. Thus, this study reveals a circulating subset of iNKT cells with NK cell–like properties distinct from conventional tissue-resident iNKT cells.

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Section: Resultssupporting

confidence: 92%

A circulating subset of iNKT cells mediates antitumor and antiviral immunity

et al. 2022

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“…The FoxN1-Cre IL-15 conditional knockout (cKO) mice, deficient in IL-15 expression in mTECs, were utilized to elucidate the thymic IL-15 niche for iNKT cells. The FoxN1-Cre IL-15 cKO mice exhibit a reduction in NKT1 cells, but not NKT2 or NKT17 cells, which aligns with a preceding study confirming the indispensability of TEC-derived IL-15 for type 1 innate-like T cells, including iNKT cells ( 92 ). Subsequently, mature stage 3 iNKT cells, which are nearly identical to NKT1 cells in mice, can be classified into three subpopulations based on the presence of the NK cell receptor CD244 (also known as 2B4 or SLAMF4) and the chemokine receptor CXCR6: CD244 + CXCR6 + double-positive C2 iNKT cells, CD244 − CXCR6 + single-positive C1 iNKT cells, and CD244 − CXCR6 − double-negative C0 iNKT cells ( 11 ).…”

Section: Thymic Il-15 Niche-dependent Circulating Inkt Cellssupporting

confidence: 89%

Insights into the heterogeneity of iNKT cells: tissue-resident and circulating subsets shaped by local microenvironmental cues

Cui,

Abe,

Kato

et al. 2024

Front. Immunol.

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Invariant natural killer T (iNKT) cells are a distinct subpopulation of innate-like T lymphocytes. They are characterized by semi-invariant T cell receptors (TCRs) that recognize both self and foreign lipid antigens presented by CD1d, a non-polymorphic MHC class I-like molecule. iNKT cells play a critical role in stimulating innate and adaptive immune responses, providing an effective defense against infections and cancers, while also contributing to chronic inflammation. The functions of iNKT cells are specific to their location, ranging from lymphoid to non-lymphoid tissues, such as the thymus, lung, liver, intestine, and adipose tissue. This review aims to provide insights into the heterogeneity of development and function in iNKT cells. First, we will review the expression of master transcription factors that define subsets of iNKT cells and their production of effector molecules such as cytokines and granzymes. In this article, we describe the gene expression profiles contributing to the kinetics, distribution, and cytotoxicity of iNKT cells across different tissue types. We also review the impact of cytokine production in distinct immune microenvironments on iNKT cell heterogeneity, highlighting a recently identified circulating iNKT cell subset. Additionally, we explore the potential of exploiting iNKT cell heterogeneity to create potent immunotherapies for human cancers in the future.

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“…1E ). Previous studies have demonstrated that IL-7 and IL-15 produced by TECs regulate the development of thymocytes and innate lymphoid cells ( 28 29 ). Based on these results, it is reasonable to hypothesize that the decreased cytokine signaling in old age TECs may contribute to the development of these subsets.…”

Section: Resultsmentioning

confidence: 99%

Comprehensive Transcriptomic Analysis for Thymic Epithelial Cells of Aged Mice and Humans

Lee,

Song,

Chung

2023

Immune Netw

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Thymic epithelial cells (TECs) play a critical role in thymic development and thymopoiesis. As individuals age, TECs undergo various changes that impact their functions, leading to a reduction in cell numbers and impaired thymic selection. These age-related alterations have been observed in both mice and humans. However, the precise mechanisms underlying age-related TEC dysfunction remain unclear. Furthermore, there is a lack of a comprehensive study that connects mouse and human biological processes in this area. To address this gap, we conducted an extensive transcriptome analysis of young and old TECs in mice, complemented by further analysis of publicly available human TEC single-cell RNA sequencing data. Our analysis revealed alterations in both known and unknown pathways that potentially contribute to age-related TEC dysfunction. Specifically, we observed downregulation of pathways related to cell proliferation, T cell development, metabolism, and cytokine signaling in old age TECs. Conversely, TGF-β, BMP, and Wnt signaling pathways were upregulated, which have been known to be associated with age-related TEC dysfunctions or newly discovered in this study. Importantly, we found that these age-related changes in mouse TECs were consistently present in human TECs as well. This cross-species validation further strengthens the significance of our findings. In conclusion, our comprehensive analysis provides valuable insight into the biological and immunological characteristics of aged TECs in both mice and humans. These findings contribute to a better understanding of thymic involution and age-induced immune dysfunction.

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Thymic Epithelial Cell-Derived IL-15 and IL-15 Receptor α Chain Foster Local Environment for Type 1 Innate Like T Cell Development

Cited by 9 publications

References 75 publications

A circulating subset of iNKT cells mediates antitumor and antiviral immunity

A circulating subset of iNKT cells mediates antitumor and antiviral immunity

Insights into the heterogeneity of iNKT cells: tissue-resident and circulating subsets shaped by local microenvironmental cues

Comprehensive Transcriptomic Analysis for Thymic Epithelial Cells of Aged Mice and Humans

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