Serine 182 on RORγt regulates T helper 17 and regulatory T cell functions to resolve inflammation

Unresolved inflammation causes tissue damage and contributes to autoimmune conditions. However, the molecules and mechanisms controlling T cell mediated inflammation remain to be fully elucidated. Here, we report an unexpected role of the RAR-Related Orphan Receptor-gamma protein (RORγt) in resolving tissue inflammation. Single-cell RNA-seq (scRNA-seq) revealed that an evolutionarily conserved serine 182 residue on ROR&γt (RORγtS182) is critical for restricting IL-1β-mediated Th17 activities and promoting anti-inflammatory cytokine IL-10 production in RORγt+ Treg cells in inflamed tissues. Phospho-null RORγtS182A knock-in mice experienced delayed recovery and succumbed to exacerbated diseases after dextran sulfate sodium (DSS) induced colitis and experimental autoimmune encephalomyelitis (EAE) challenge. Together, these results highlight the essential role of ROR&γtS182 in resolving T cell mediated tissue inflammation, providing a potential therapeutic target to combat autoimmune diseases.

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The role of Th17/Treg-mediated immunoregulation in abortion mice

European Journal of Inflammation ◽

10.1177/2058739218760354 ◽

2018 ◽

Vol 16 ◽

pp. 205873921876035 ◽

Cited By ~ 2

Author(s):

Ning Li ◽

Qinglan Qu ◽

Qian Yan

Keyword(s):

Spontaneous Abortion ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Normal Pregnancy ◽

Treg Cells ◽

Vital Role ◽

Orphan Receptor ◽

T Helper ◽

T Helper 17

In the study, we investigated the immune factors related to T helper 17 (Th17) cells and T regulatory (Treg) cells in spontaneous abortion mice. The expression of Th17 was analyzed by interleukin (IL)-6, IL-17A secretion, RAR-related orphan receptor γt (RORγt) expression, and proportion of CD4+IL-17+ cells. The levels of IL-10, transforming growth factor β (TGF-β), Foxp3, and CD4+Foxp3+ cells were presented the Treg expression. Higher embryo absorption rate was found in spontaneous abortion group than that in normal pregnancy group ( P < 0.01). Compared with the normal pregnancy mice, spontaneous abortion mice showed higher levels of IL-6 and IL-17A and lower levels of IL-10 and TGF-β in serum and in decidua ( P < 0.05). Furthermore, the expressions of Foxp3 and CD4+Foxp3+ cells were significantly decreased in spontaneous abortion mice than those in normal pregnancy mice ( P < 0.05). However, the levels of RORγt and CD4+IL-17+ cells remarkably increased in spontaneous abortion mice ( P < 0.05). The results reveal that Th17/Treg cells may play a vital role in immunoregulation during pregnancy.

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Regulation of IL-17 in chronic inflammation in the human lung

Clinical Science ◽

10.1042/cs20100417 ◽

2011 ◽

Vol 120 (12) ◽

pp. 515-524 ◽

Cited By ~ 32

Author(s):

Carol Pridgeon ◽

Laurence Bugeon ◽

Louise Donnelly ◽

Ursula Straschil ◽

Susan J. Tudhope ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Lung Tissue ◽

Mononuclear Cells ◽

Human Lung ◽

Treg Cells ◽

Orphan Receptor ◽

Th2 Cells ◽

Chronic Obstructive ◽

Interleukin 17

The regulation of human Th17 cell effector function by Treg cells (regulatory T-cells) is poorly understood. In the present study, we report that human Treg (CD4+CD25+) cells inhibit the proliferative response of Th17 cells but not their capacity to secrete IL (interleukin)-17. However, they could inhibit proliferation and cytokine production by Th1 and Th2 cells as determined by IFN-γ (interferon-γ) and IL-5 biosynthesis. Currently, as there is interest in the role of IL-17-producing cells and Treg cells in chronic inflammatory diseases in humans, we investigated the presence of CD4+CD25+ T-cells and IL-17 in inflammation in the human lung. Transcripts for IL-17 were expressed in mononuclear cells and purified T-cells from lung tissue of patients with chronic pulmonary inflammation and, when activated, these cells secrete soluble protein. The T-cell-specific transcription factors RORCv2 (retinoic acid-related orphan receptor Cv2; for Th17) and FOXP3 (forkhead box P3; for Treg cells) were enriched in the T-cell fraction of lung mononuclear cells. Retrospective stratification of the patient cohort into those with COPD (chronic obstructive pulmonary disease) and non-COPD lung disease revealed no difference in the expression of IL-17 and IL-23 receptor between the groups. We observed that CD4+CD25+ T-cells were present in comparable numbers in COPD and non-COPD lung tissue and with no correlation between the presence of CD4+CD25+ T-cells and IL-17-producing cells. These results suggest that IL-17-expressing cells are present in chronically inflamed lung tissue, but there is no evidence to support this is due to the recruitment or expansion of Treg cells.

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Intranasal peptide-induced peripheral tolerance: the role of IL-10 in regulatory T cell function within the context of experimental autoimmune encephalomyelitis

Veterinary Immunology and Immunopathology ◽

10.1016/s0165-2427(02)00068-5 ◽

2002 ◽

Vol 87 (3-4) ◽

pp. 357-372 ◽

Cited By ~ 26

Author(s):

Emma J Massey ◽

Anette Sundstedt ◽

Michael J Day ◽

Gaynor Corfield ◽

Stephen Anderton ◽

...

Keyword(s):

T Cell ◽

Experimental Autoimmune Encephalomyelitis ◽

Regulatory T Cell ◽

Cell Function ◽

Peripheral Tolerance ◽

Autoimmune Encephalomyelitis ◽

T Cell Function ◽

Experimental Autoimmune

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The role of ferroptosis in breast cancer patients: a comprehensive analysis

Cell Death Discovery ◽

10.1038/s41420-021-00473-5 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Zeng-Hong Wu ◽

Yun Tang ◽

Hong Yu ◽

Hua-Dong Li

Keyword(s):

Breast Cancer ◽

T Cell ◽

Signaling Pathway ◽

Differentially Expressed Genes ◽

Function Analysis ◽

Cancer Prognosis ◽

Differentially Expressed ◽

Immune Checkpoints ◽

Cell Functions

AbstractBreast cancer (BC) affects the breast tissue and is the second most common cause of mortalities among women. Ferroptosis is an iron-dependent cell death mode that is characterized by intracellular accumulation of reactive oxygen species (ROS). We constructed a prognostic multigene signature based on ferroptosis-associated differentially expressed genes (DEGs). Moreover, we comprehensively analyzed the role of ferroptosis-associated miRNAs, lncRNAs, and immune responses. A total of 259 ferroptosis-related genes were extracted. KEGG function analysis of these genes revealed that they were mainly enriched in the HIF-1 signaling pathway, NOD-like receptor signaling pathway, central carbon metabolism in cancer, and PPAR signaling pathway. Fifteen differentially expressed genes (ALOX15, ALOX15B, ANO6, BRD4, CISD1, DRD5, FLT3, G6PD, IFNG, NGB, NOS2, PROM2, SLC1A4, SLC38A1, and TP63) were selected as independent prognostic factors for BC patients. Moreover, T cell functions, including the CCR score, immune checkpoint, cytolytic activity, HLA, inflammation promotion, para-inflammation, T cell co-stimulation, T cell co-inhibition, and type II INF responses were significantly different between the low-risk and high-risk groups of the TCGA cohort. Immune checkpoints between the two groups revealed that the expressions of PDCD-1 (PD-1), CTLA4, LAG3, TNFSF4/14, TNFRSF4/8/9/14/18/25, and IDO1/2 among others were significantly different. A total of 1185 ferroptosis-related lncRNAs and 219 ferroptosis-related miRNAs were also included in this study. From the online database, we identified novel ferroptosis-related biomarkers for breast cancer prognosis. The findings of this study provide new insights into the development of new reliable and accurate cancer treatment options.

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Pivotal Roles of T-Helper 17-Related Cytokines, IL-17, IL-22, and IL-23, in Inflammatory Diseases

Clinical and Developmental Immunology ◽

10.1155/2013/968549 ◽

2013 ◽

Vol 2013 ◽

pp. 1-13 ◽

Cited By ~ 75

Author(s):

Ning Qu ◽

Mingli Xu ◽

Izuru Mizoguchi ◽

Jun-ichi Furusawa ◽

Kotaro Kaneko ◽

...

Keyword(s):

Th17 Cell ◽

Th17 Cells ◽

Functional Role ◽

Inflammatory Diseases ◽

Interleukin 17 ◽

T Helper ◽

T Helper 17 ◽

Autoimmune Encephalomyelitis ◽

Experimental Autoimmune

T-helper 17 (Th17) cells are characterized by producing interleukin-17 (IL-17, also called IL-17A), IL-17F, IL-21, and IL-22 and potentially TNF-α and IL-6 upon certain stimulation. IL-23, which promotes Th17 cell development, as well as IL-17 and IL-22 produced by the Th17 cells plays essential roles in various inflammatory diseases, such as experimental autoimmune encephalomyelitis, rheumatoid arthritis, colitis, and Concanavalin A-induced hepatitis. In this review, we summarize the characteristics of the functional role of Th17 cells, with particular focus on the Th17 cell-related cytokines such as IL-17, IL-22, and IL-23, in mouse models and human inflammatory diseases.

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m6A demethylase ALKBH5 controls CD4+ T cell pathogenicity and promotes autoimmunity

Science Advances ◽

10.1126/sciadv.abg0470 ◽

2021 ◽

Vol 7 (25) ◽

pp. eabg0470

Author(s):

Jing Zhou ◽

Xingli Zhang ◽

Jiajia Hu ◽

Rihao Qu ◽

Zhibin Yu ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Messenger Rna ◽

Interferon Γ ◽

Autoimmune Encephalomyelitis ◽

Cell Responses ◽

Chemokine Ligand ◽

The Central Nervous System ◽

Chemokine Ligand 2

N6-methyladenosine (m6A) modification is dynamically regulated by “writer” and “eraser” enzymes. m6A “writers” have been shown to ensure the homeostasis of CD4+ T cells, but the “erasers” functioning in T cells is poorly understood. Here, we reported that m6A eraser AlkB homolog 5 (ALKBH5), but not FTO, maintains the ability of naïve CD4+ T cells to induce adoptive transfer colitis. In addition, T cell–specific ablation of ALKBH5 confers protection against experimental autoimmune encephalomyelitis. During the induced neuroinflammation, ALKBH5 deficiency increased m6A modification on interferon-γ and C-X-C motif chemokine ligand 2 messenger RNA (mRNA), thus decreasing their mRNA stability and protein expression in CD4+ T cells. These modifications resulted in attenuated CD4+ T cell responses and diminished recruitment of neutrophils into the central nervous system. Our findings reveal an unexpected specific role of ALKBH5 as an m6A eraser in controlling the pathogenicity of CD4+ T cells during autoimmunity.

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Differential Levels of Regulatory T Cells and T-Helper-17 Cells in Women With Early and Advanced Endometriosis

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2019-00350 ◽

2019 ◽

Vol 104 (10) ◽

pp. 4715-4729 ◽

Cited By ~ 8

Author(s):

Khaleque N Khan ◽

Kazuo Yamamoto ◽

Akira Fujishita ◽

Hideki Muto ◽

Akemi Koshiba ◽

...

Keyword(s):

T Cell ◽

Th17 Cells ◽

Treg Cells ◽

Lower Percentage ◽

T Helper ◽

T Helper 17 ◽

Control Subjects ◽

Cell Subpopulations ◽

American Society ◽

T Cell Subpopulations

Abstract Context Regulatory T (Treg) cells and T-helper-17 (Th17) cells may be involved in endometriosis. Information on the pattern of change in the percentages of Treg and Th17 cells in the peripheral blood (PB) and peritoneal fluid (PF) of women with early and advanced endometriosis is unclear. Objective To investigate the pattern of change in the percentages of Treg and Th17 cells in the PB and PF of women with early and advanced endometriosis. Methods We recruited 31 women with laparoscopically and histologically confirmed, revised American Society of Reproductive Medicine stage I-II endometriosis, 39 women with stage III-IV endometriosis, and 36 control subjects without visible endometriosis. PB and PF samples were collected and T-cell subpopulations analyzed by flow cytometry using specific monoclonal antibodies recognizing CD4+, CD25+, FOXP3+, and IL-17A+ markers. PF concentrations of TGF-β and IL-17 were measured by ELISA. Results The percentages of CD25+FOXP3+ Treg cells within the CD4+ T-cell population were significantly higher in the PF of women with advanced endometriosis than in either early endometriosis or in control subjects (P < 0.05 for both). A persistently lower percentage of CD4+IL-17A+ Th17 cells was found in both PB and PF of women with early and advanced endometriosis. Compared with IL-17 levels, PF levels of TGF-β were significantly higher in women with endometriosis (P = 0.01). Conclusion Our findings reconfirmed the current speculation that endometriosis is related to alteration of Treg and Th17 cells in the pelvis causing survival and implantation of ectopic endometrial lesions.

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Role of Phosphodiesterase 7 (PDE7) in T Cell Activity. Effects of Selective PDE7 Inhibitors and Dual PDE4/7 Inhibitors on T Cell Functions

International Journal of Molecular Sciences ◽

10.3390/ijms21176118 ◽

2020 ◽

Vol 21 (17) ◽

pp. 6118 ◽

Cited By ~ 1

Author(s):

Marianna Szczypka

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Splice Variants ◽

Cell Activity ◽

Cell Functions ◽

Simultaneous Inhibition ◽

And Function

Phosphodiesterase 7 (PDE7), a cAMP-specific PDE family, insensitive to rolipram, is present in many immune cells, including T lymphocytes. Two genes of PDE7 have been identified: PDE7A and PDE7B with three or four splice variants, respectively. Both PDE7A and PDE7B are expressed in T cells, and the predominant splice variant in these cells is PDE7A1. PDE7 is one of several PDE families that terminates biological functions of cAMP—a major regulating intracellular factor. However, the precise role of PDE7 in T cell activation and function is still ambiguous. Some authors reported its crucial role in T cell activation, while according to other studies PDE7 activity was not pivotal to T cells. Several studies showed that inhibition of PDE7 by its selective or dual PDE4/7 inhibitors suppresses T cell activity, and consequently T-mediated immune response. Taken together, it seems quite likely that simultaneous inhibition of PDE4 and PDE7 by dual PDE4/7 inhibitors or a combination of selective PDE4 and PDE7 remains the most interesting therapeutic target for the treatment of some immune-related disorders, such as autoimmune diseases, or selected respiratory diseases. An interesting direction of future studies could also be using a combination of selective PDE7 and PDE3 inhibitors.

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