High-parametric evaluation of human invariant natural killer T cells to delineate heterogeneity in allo- and autoimmunity

Erkers, Tom; Xie, Bryan J.; Kenyon, Laura; Smith, Brian R.; Rieck, Mary; Jensen, Kent; Ji, Xuhuai; Basina, Marina; Strober, Samuel; Negrin, Robert S.; Maecker, Holden T.; Meyer, Everett

doi:10.1182/blood.2019001903

Cited by 14 publications

(18 citation statements)

References 37 publications

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“…We did not identify any clear enrichment of iNKT17-signature expressing cells in either cluster 0 or cluster 1 (Figure 3, bottom panel). To further validate the iNKT-sublineages signatures we generated, we next assessed them on publicly available scRNA-seq data of iNKT cells isolated from human peripheral blood (Erkers et al, 2020). Our analysis clearly identified a cluster of iNKT cells displaying an enrichment in iNKT1-signature genes (Supplemental Figure 2A,B) while we observed the presence of some cells enriched in iNKT2- and iNKT17-signature genes not associated with any specific cluster.…”

Section: Resultsmentioning

confidence: 99%

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Single-cell Transcriptomics Reveal Different Maturation Stages and Sublineages Commitment of Human Thymic Invariant Natural Killer T cells

Maas‐Bauer

Acharya

Baker

et al. 2022

Preprint

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Invariant natural killer T (iNKT) cells are a subset of heterogenous T-cells with potent cytotoxic and immunomodulatory properties. During thymic development, murine iNKT cells go through different maturation stages and differentiate into distinct sublineages, namely iNKT1, iNKT2, and iNKT17 cells. To define maturation stages and to assess sublineage commitment of human iNKT cells during thymic development, we performed single-cell RNA sequencing analysis on human thymic iNKT cells. We show that these iNKT cells displayed heterogeneity and unsupervised analysis identified two clusters: one with an immature profile with high expression of genes that are important for iNKT cell development and enriched in cells expressing an iNKT2 signature, whereas a second cluster displayed a mature, terminally differentiated profile resembling murine iNKT1 cells. Trajectory analysis suggested an ontological relationship between the two clusters. Our work provides the first single cell transcriptomic analysis of thymic human iNKT cells offering new insights into their developmental process in humans.

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Section: Resultsmentioning

confidence: 99%

“…Pseudotime analysis was performed using the Monocle3 package. Previously published scRNA-seq datasets from human iNKT cells recovered from the peripheral blood (PRJNA563899, PRJNA565590; (Erkers et al, 2020)) were analyzed using the same pipeline. 2020) showing distinct clusters of human iNKT cells from peripheral blood.…”

Section: Single Cell Rna Sequencingmentioning

confidence: 99%

Single-cell Transcriptomics Reveal Different Maturation Stages and Sublineages Commitment of Human Thymic Invariant Natural Killer T cells

Maas‐Bauer

Acharya

Baker

et al. 2022

Preprint

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“…Recently, Erkers et al 38 reported an extensive characterization of human iNKT heterogeneity and identified a CD4 -CD94 1 population with iNKT1-like properties and a CD4 1 population producing higher levels of IL-4. Due to the paucity of iNKT cells in human peripheral blood, current clinical trials using iNKT cells involve in vitro expansion protocols (#NCT03605953).…”

Section: Discussionmentioning

confidence: 99%

Invariant natural killer T-cell subsets have diverse graft-versus-host-disease–preventing and antitumor effects

Maas‐Bauer

Lohmeyer

Hirai

et al. 2021

Blood

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Invariant Natural Killer T (iNKT) cells are a T cell subset with potent immunomodulatory properties. Experimental evidence in mice and observational studies in humans indicate that iNKT cells have antitumor potential as well as the ability to suppress acute and chronic Graft-versus-Host-Disease (GvHD). Murine iNKT cells differentiate during thymic development into iNKT1, iNKT2 and iNKT17 sublineages, which differ transcriptomically and epigenomically, and have subset-specific developmental requirements. Whether distinct iNKT sublineages also differ in their antitumor effect and their ability to suppress GvHD is currently unknown. In this work, we generated highly purified murine iNKT-sublineages, characterized their transcriptomic and epigenomic landscape, and assessed specific functions. We demonstrate that iNKT2 and iNKT17, but not iNKT1 cells, efficiently suppress T cell activation in vitro and mitigate murine acute GvHD in vivo. Conversely, we show that iNKT1 cells display the highest antitumor activity against murine B-cell lymphoma cells both in vitro and in vivo. Thus, we demonstrate for the first time that iNKT sublineages have distinct and different functions, with iNKT1 cells having the highest antitumor activity and iNKT2 and iNKT17 cells having immune-regulatory properties. These results have important implications for the translation of iNKT cell therapies to the clinic for cancer immunotherapy as well as for GvHD prevention and treatment.

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“…Similar to their murine counterparts, most human iNKT cells express PLZF ( 80 – 82 ), and are characterized by an innate-like transcriptional profile that results in a “poised-effector” status allowing them to rapidly mediate functional responses ( 83 ). Multi-parameter flow cytometric analyses and gene expression studies have revealed human iNKT cells to express a diverse selection of cytokines and chemokines ( 84 – 88 ). Human iNKT cells can be segregated into two major subsets according to CD4 expression ( 84 , 85 ).…”

Section: What Determines the Nature Of The Functional Response Mediat...mentioning

confidence: 99%

Harnessing invariant natural killer T cells to control pathological inflammation

Bharadwaj

Gumperz

2022

Front. Immunol.

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Invariant natural killer T (iNKT) cells are innate T cells that are recognized for their potent immune modulatory functions. Over the last three decades, research in murine models and human observational studies have revealed that iNKT cells can act to limit inflammatory pathology in a variety of settings. Since iNKT cells are multi-functional and can promote inflammation in some contexts, understanding the mechanistic basis for their anti-inflammatory effects is critical for effectively harnessing them for clinical use. Two contrasting mechanisms have emerged to explain the anti-inflammatory activity of iNKT cells: that they drive suppressive pathways mediated by other regulatory cells, and that they may cytolytically eliminate antigen presenting cells that promote excessive inflammatory responses. How these activities are controlled and separated from their pro-inflammatory functions remains a central question. Murine iNKT cells can be divided into four functional lineages that have either pro-inflammatory (NKT1, NKT17) or anti-inflammatory (NKT2, NKT10) cytokine profiles. However, in humans these subsets are not clearly evident, and instead most iNKT cells that are CD4+ appear oriented towards polyfunctional (TH0) cytokine production, while CD4- iNKT cells appear more predisposed towards cytolytic activity. Additionally, structurally distinct antigens have been shown to induce TH1- or TH2-biased responses by iNKT cells in murine models, but human iNKT cells may respond to differing levels of TCR stimulation in a way that does not neatly separate TH1 and TH2 cytokine production. We discuss the implications of these differences for translational efforts focused on the anti-inflammatory activity of iNKT cells.

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High-parametric evaluation of human invariant natural killer T cells to delineate heterogeneity in allo- and autoimmunity

Cited by 14 publications

References 37 publications

Single-cell Transcriptomics Reveal Different Maturation Stages and Sublineages Commitment of Human Thymic Invariant Natural Killer T cells

Single-cell Transcriptomics Reveal Different Maturation Stages and Sublineages Commitment of Human Thymic Invariant Natural Killer T cells

Invariant natural killer T-cell subsets have diverse graft-versus-host-disease–preventing and antitumor effects

Harnessing invariant natural killer T cells to control pathological inflammation

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