Glucocorticoids Oppose Thymocyte Negative Selection by Inhibiting Helios and Nur77

Mittelstadt, Paul R.; Taves, Matthew D.; Ashwell, Jonathan D.

doi:10.4049/jimmunol.1900559

Cited by 9 publications

(6 citation statements)

References 57 publications

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“…This observation led us to investigate the expression of Treg-specific markers in End#6 cells using a modified antibody panel (Supplementary Table Mass panel 2). After we gated the relevant populations and visualized them in the vaevictis plot (Supplementary Figure 6), we observed that FOXP3 (transcription factor of Treg cells) and Helios (transcription factor shown to be upregulated upon negative selection in mice ( 21,64,65 )) is expressed by the CD25 pos CD127 neg immature Treg cells as well as by the CD25 hi CD127 pos End#6 cells (Figure 5E). Therefore, we hypothesized that End#6 cells constitute a specific Treg population (Figure 5D and 5E).…”

Section: Resultsmentioning

confidence: 99%

Deconstructing Complexity: A Computational Topology Approach to Trajectory Inference in the Human Thymus withtviblindi

Stuchly,

Novak,

Brdickova

et al. 2023

Preprint

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Interpreting and understanding complex, organ-level mass cytometry datasets represents a formidable interdisciplinary challenge. This study aims to identify, describe, and interpret potential developmental trajectories of thymocytes and mature T cells. We developedtviblindi, a trajectory inference algorithm that integrates several autonomous modules - pseudotime inference, random walk simulations, real-time topological classification using persistence homology, and autoencoder-based 2D visualization using thevaevictisalgorithm. This integration facilitates an interactive exploration of developmental trajectories. The utility and proficiency oftviblindiare demonstrated through comprehensive analysis of the thymic and peripheral T-cell compartment. Our approach not only uncovers and elucidates the canonical CD4 and CD8 development but also offers insights into various checkpoints such as TCRβ selection and positive/negative selection, elucidating the crossroads between further development and apoptosis. Finally, we identify and thoroughly characterize thymic regulatory T cells, tracing their development from the negative selection stage to mature thymic regulatory T cells with an extensive proliferation history and an immunophenotype of activated and recirculating cells.tviblindiis a versatile and generic approach suitable for any single-cell dataset, equipping biologists with an effective tool for interpreting complex data.

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Section: Resultsmentioning

confidence: 99%

Deconstructing Complexity: A Computational Topology Approach to Trajectory Inference in the Human Thymus withtviblindi

Stuchly,

Novak,

Brdickova

et al. 2023

Preprint

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“…The Nur77 and Helios transcription factors are upregulated in thymocytes upon the TcR/CD28 stimulation, inducing negative selection. Interestingly, glucocorticoids inhibit upregulation of Helios and Nur77 in negatively selected TcR‐stimulated mouse thymocytes 81 . Also, self‐reactive T cells in the thymus are not immature, as suggested by the SNS model, rather they have matured into CD4 + or CD8 + T cells from immature CD4 + CD8 + T cells during positive selection.…”

Section: Central Tolerance: the Adaptation Modelmentioning

confidence: 98%

“…Interestingly, glucocorticoids inhibit upregulation of Helios and Nur77 in negatively selected TcR-stimulated mouse thymocytes. 81 Also, selfreactive T cells in the thymus are not immature, as suggested by the SNS model, rather they have matured into CD4 + or CD8 + T cells from immature CD4 + CD8 + T cells during positive selection. The maturation markers RANK ligand (RANKL) and CD40 ligand are detected on thymic T cells.…”

Section: Adaptation Modelmentioning

confidence: 99%

The adaptation model of immunity: Is the goal of central tolerance to eliminate defective T cells or self‐reactive T cells?

Manjili

2022

Scand J Immunol

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The self-non-self model and the danger model are designed to understand how an immune response is induced. These models are not meant to predict if an immune response may succeed or fail in destroying/controlling its target. However, these immunological models rely on either self-antigens or self-dendritic cells for understanding of central tolerance, which have been discussed by Fuchs and Matzinger in response to Al-Yassin. In an attempt to address some questions that these models are facing when it comes to understanding central tolerance, I propose that the goal of negative selection in the thymus is to eliminate defective T cells but not self-reactive T cells. Therefore, any escape from negative selection could increase lymphopenia because of the depletion of defective naïve T cells outside the thymus, as seen in the elderly.

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“…Closely related to thymocyte selection are glucocorticoids, where glucocorticoids oppose thymocyte negative selection. 21 Adipocyte CD40-deficiency did not result in structural changes to the adrenals (Supp. Fig.…”

Section: Adipocyte Cd40-deficiency Decreases Haematopoiesis and Incre...mentioning

confidence: 99%

Adipocytes control hematopoiesis and inflammation through CD40 signaling

et al. 2022

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The co-stimulatory CD40-CD40L dyad plays an important role in chronic inflammatory diseases associated with ageing. Although CD40 is mainly expressed by immune cells, CD40 is also present on adipocytes. We aimed to delineate the role of adipocyte-CD40 in the aging haematopoietic system and evaluated the effects of adipocyte CD40 deficiency on cardiometabolic diseases. Adult adipocyte CD40-deficient mice (AdiCD40KO) mice had a decrease in bone marrow (BM) haematopoietic stem cells (Lin-Sca+cKit+, LSK) and common lymphoid progenitors, which was associated with increased BM adiposity and T-cell activation, along with elevated plasma corticosterone levels, a phenotype that became more pronounced with age. Atherosclerotic AdiCD40koApoE-/- (CD40AKO) mice also displayed changes in the LSK population, showing increased myeloid- and lymphoid multipotent progenitors, and augmented corticosterone levels. Increased T-cell activation could be observed in BM, spleen, and adipose tissue (AT), while B-cell numbers were decreased. Although atherosclerosis was reduced in CD40AKO mice, plaques contained more activated T-cells and larger necrotic cores. Analysis of peripheral AT in a diet-induced obesity model revealed that obese AdiCD40KO mice showed increased T-cell activation in AT and lymphoid organs, but exhibited decreased weight gain and improved insulin sensitivity, along with increased fat oxidation. In conclusion, adipocyte CD40 plays an important role in maintaining immune cell homeostasis in BM during ageing and chronic inflammatory diseases, particularly of the lymphoid populations. Although adipocyte CD40-deficiency reduces atherosclerosis burden and ameliorates diet-induced obesity, the accompanying T-cell activation may eventually aggravate cardiometabolic diseases.

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Glucocorticoids Oppose Thymocyte Negative Selection by Inhibiting Helios and Nur77

Cited by 9 publications

References 57 publications

Deconstructing Complexity: A Computational Topology Approach to Trajectory Inference in the Human Thymus withtviblindi

Deconstructing Complexity: A Computational Topology Approach to Trajectory Inference in the Human Thymus withtviblindi

The adaptation model of immunity: Is the goal of central tolerance to eliminate defective T cells or self‐reactive T cells?

Adipocytes control hematopoiesis and inflammation through CD40 signaling

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