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Key Event: 2324

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Increased of Treg/Th17 cell ratio

Short name

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Dysregulation of Treg/Th17 cell ratio

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Biological Context

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Level of Biological Organization
Cellular

Cell term

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Organ term

Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor). Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Overview

AOPs Including This Key Event

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AOP Name	Role of event in AOP	Point of Contact	Author Status	OECD Status
AhR activation leading to cancer progression	KeyEvent	Léo SPORTES-MILOT (send email)	Under development: Not open for comment. Do not cite

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Life Stages

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Sex Applicability

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Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

The ratio between Th17 and T regulatory (Treg) cells is essential for maintaining a balanced immune environment (Noack and Miossec, 2014; Fasching et al., 2017; Lee, 2018). Both cells are derived from CD4+ lymphocytes, a subset of T lymphocytes.

On one hand, the role of Treg is to dampen the immune response by tempering the activity of CTLs, also called CD8+ cytotoxic T cells. Tregs are induced by TGF-β and FoxP3 (Forkhead box P3), which plays a major role in the activation from the naïve state to the activated Treg state. Consequently, the expression of FoxP3 well reflects the Treg activity (Fontenot et al., 2003); they are also characterized by a high expression of CD25 (Interleukin 2 receptor ɑ-chain). To highlight their immunosuppressive role in the TME, their elimination has been shown to lead to tumor immunity (Shimizu et al., 1999).

On the other hand, the role of Th17 cells is to enhance the immune response by producing pro-inflammatory signals like IL-17, IL-22, or IL-23. Naive T cells are also activated partly by TGF-β, but a co-stimulation with IL-6 or IL-21 is necessary; indeed, the absence of these proinflammatory cytokines leads to Treg differentiation instead (Bettelli et al., 2006).

In short, both Th17 and Treg require TGF-β to be activated; however, in a stressed environment, the production of IL-6 by other immune cells leads to a preferential differentiation towards the Th17 phenotype.

In cancer or in autoimmune diseases, this balance between the two phenotypes is disturbed with a higher presence of Treg and leads to adverse outcomes such as tumor maintenance (Lin et al., 2019; He et al., 2020; Yan et al., 2020).

How It Is Measured or Detected

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1. Multiparameter flow cytometry. This is the most widely used and highest-confidence method. Treg cells are identified as CD4+CD25+FoxP3+, while Th17 cells are identified either by intracellular IL-17A staining, or by expression of the lineage-defining transcription factor RORγt (Maruyama et al., 2010; Zeng et al., 2020). The Treg/Th17 ratio is then calculated as the proportion of Tregs divided by the proportion of Th17 cells among total CD4+ cells, in a given tissue compartment (tumor, lymph node, or peripheral blood). 2. Immunohistochemistry (IHC). Used on formalin-fixed tumor sections to localize and semi-quantify FoxP3+, IL-17+ or RORγt+ cell infiltrates directly within the tumor microenvironment, complementing flow-cytometric data obtained from dissociated tissue (Maruyama et al., 2010; Zeng et al., 2020). 3. Quantitative RT-PCR. Used to measure relative transcript levels of FOXP3 and RORC (encoding RORγt) as surrogate, whole tissue indicators of Treg versus Th17 lineage commitment (Qin et al., 2017). 4. ELISA / cytokine profiling. Serum or culture-supernatant levels of IL-17 and IL-23 (Th17-associated) can be measured by ELISA as functional correlates of Th17 activity, typically alongside flow-cytometric Treg quantification (He et al., 2011).

Domain of Applicability

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References

List of the literature that was cited for this KE description. More help

Bettelli, Estelle, Yijun Carrier, Wenda Gao, et al. 2006. « Reciprocal Developmental Pathways for the Generation of Pathogenic Effector TH17 and Regulatory T Cells ». Nature 441 (7090): 235‑38. https://doi.org/10.1038/nature04753.

Fasching, Patrizia, Martin Stradner, Winfried Graninger, Christian Dejaco, et Johannes Fessler. 2017. « Therapeutic Potential of Targeting the Th17/Treg Axis in Autoimmune Disorders ». Molecules (Basel, Switzerland) 22 (1): 134. https://doi.org/10.3390/molecules22010134.

Fontenot, Jason D., Marc A. Gavin, et Alexander Y. Rudensky. 2003. « Foxp3 Programs the Development and Function of CD4+CD25+ Regulatory T Cells ». Nature Immunology 4 (4): 330‑36. https://doi.org/10.1038/ni904.

He, Songbing, Min Fei, Yugang Wu, et al. 2011. « Distribution and Clinical Significance of Th17 Cells in the Tumor Microenvironment and Peripheral Blood of Pancreatic Cancer Patients ». International Journal of Molecular Sciences 12 (11): 7424‑37. https://doi.org/10.3390/ijms12117424.

He, Xin, Bo Liang, et Ning Gu. 2020. « Th17/Treg Imbalance and Atherosclerosis ». Disease Markers 2020: 8821029. https://doi.org/10.1155/2020/8821029.

Lee, Gap Ryol. 2018. « The Balance of Th17 versus Treg Cells in Autoimmunity ». International Journal of Molecular Sciences 19 (3): 730. https://doi.org/10.3390/ijms19030730.

Lin, Wei, Zhaoyuan Niu, Hualing Zhang, et al. 2019. « Imbalance of Th1/Th2 and Th17/Treg during the Development of Uterine Cervical Cancer ». International Journal of Clinical and Experimental Pathology 12 (9): 3604‑12.

Maruyama, Takanori, Koji Kono, Yoshiki Mizukami, et al. 2010. « Distribution of Th17 cells and FoxP3(+) regulatory T cells in tumor‐infiltrating lymphocytes, tumor‐draining lymph nodes and peripheral blood lymphocytes in patients with gastric cancer ». Cancer Science 101 (9): 1947‑54. https://doi.org/10.1111/j.1349-7006.2010.01624.x.

Noack, Mélissa, et Pierre Miossec. 2014. « Th17 and regulatory T cell balance in autoimmune and inflammatory diseases ». Autoimmunity Reviews 13 (6): 668‑77. https://doi.org/10.1016/j.autrev.2013.12.004.

Qin, Jing, Jin Zhou, Chenling Fan, et al. 2017. « Increased Circulating Th17 but Decreased CD4+Foxp3+ Treg and CD19+CD1dhiCD5+ Breg Subsets in New-Onset Graves’ Disease ». BioMed Research International 2017: 8431838. https://doi.org/10.1155/2017/8431838.

Shimizu, Jun, Sayuri Yamazaki, Takeshi Takahashi, Yasumasa Ishida, et Shimon Sakaguchi. 2002. « Stimulation of CD25+CD4+ Regulatory T Cells through GITR Breaks Immunological Self-Tolerance ». Nature Immunology 3 (2): 135‑42. https://doi.org/10.1038/ni759.

Yan, Jun-Bin, Min-Min Luo, Zhi-Yun Chen, et Bei-Hui He. 2020. « The Function and Role of the Th17/Treg Cell Balance in Inflammatory Bowel Disease ». Journal of Immunology Research 2020: 8813558. https://doi.org/10.1155/2020/8813558.

Zeng, Rong, Yi Lyu, Heng Niu, Kunxian Yang, et Xinmin Yan. 2020. « FoxP3 promotes lymph node metastasis in patients with papillary thyroid carcinoma complicated with Hashimoto’s thyroiditis ». Translational Cancer Research 9 (3): 1337‑50. https://doi.org/10.21037/tcr.2020.01.12.