The role of IL-27/Lag3 axis in regulating Foxp3+ regulatory T cell function

IL-27/Lag3轴在调节Foxp3调节性T细胞功能中的作用

• 批准号: 10264303
• 负责人: Booki Min
• 金额: $ 39.75万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-15 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10264303
• 关键词: Affect; Animal Model; Animals; Antigen-Presenting Cells; Antigens; Attenuated; Autoantigens; Autoimmune Diseases; CD4 Positive T Lymphocytes; Cell physiology; Cells; Chronic; Clinical; Defect; Development; Disease; Disease model; Experimental Autoimmune Encephalomyelitis; FOXP3 gene; Family; Gene Activation; Generations; Goals; Histologic; Immune response; Immunity; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Interleukin-10; Interleukin-12; Intestines; Lymphocyte Activation; Mediating; Microarray Analysis; Multiple Sclerosis; Mus; Myelin; Neuraxis; Pathogenesis; Pathway interactions; Play; Recovery; Regulation; Regulatory T-Lymphocyte; Reporting; Role; Severities; Signal Pathway; Signal Transduction; T cell regulation; T cell response; T-Cell Activation; Testing; Tissues; autoimmune inflammation; cell type; cytokine; genome-wide; immune activation; immunoregulation; improved; in vivo; multiple sclerosis patient; neuroinflammation; novel; novel strategies; prevent; response; targeted treatment

Abstract Foxp3+ CD4 T cells (Tregs) play a key role in regulating immunity and tolerance. Defects in Treg generation and/or functions are directly associated with uncontrolled immune activation leading to the development of autoimmune diseases. Yet, the precise mechanisms by which Tregs express the functions remain unclear. Multiple sclerosis (MS) is a myelin antigen specific autoimmune inflammation of the central nervous system (CNS) mediated by myelin antigen specific Th17 type CD4 T cells. Experimental autoimmune encephalomyelitis (EAE) is an animal model that shares clinical and histological features with MS, and is widely used to investigate the pathogenesis as well as to develop an approach to treat the disease. Increasing evidence suggests that Treg function may be dysregulated in MS patients or EAE bearing mice. Thus, identifying pathways that improve Treg function is an issue of clinical importance to develop a potential therapy targeting Tregs. The major goal of this application is to test the role of IL-27 in Treg function. We recently reported that IL-27 signaling in Tregs plays an essential role in suppressing Th17 type inflammation in the intestine. We utilized a newly developed Treg-specific Il27ra-/- animal and found that Treg-specific IL-27R deficiency results in a severe EAE. CNS infiltrating CD4 T cells producing proinflammatory cytokines were uncontrolled in the presence of Il27ra-/- Tregs, while IL-10+ CD4 T cells implicated in regulation of inflammatory responses remained unchanged. Genome wide microarray analysis revealed that IL-27 stimulation in Tregs induces Lag3, a CD4 like molecule implicated in negative regulation of T cell activation. We then used a novel Treg-specific Lag3-/- animal and found that they also develop severe EAE, suggesting that Treg expression of Lag3 may be critical to mediate IL-27-induced Treg function. Finally, IL-27 prestimulation in Tregs significantly enhances suppressive function both in vitro and in vivo. The overall hypothesis is that IL-27 controls Treg suppressive function during EAE and that Lag3 induced by IL-27 signaling plays a key role in mediating IL-27 effect on Tregs. We also propose that the suppressive function of Tregs can be improved by IL-27 prestimulation, reversing ongoing inflammation in the CNS. Three specific aims are proposed. Aim #1 will test the role of IL-27 signaling on Treg function during EAE. Aim #2 will test To test the role of Lag3 during IL-27-mediated control of Treg function. Aim #3 will test the mechanisms by which IL-27 prestimulated Tregs efficiently reverse ongoing neuroinflammation. We anticipate that the results from this study will identify novel mechanisms by which IL-27 modulates Treg function via Lag3 to downregulate inflammation in the CNS. Completing the proposed studies will provide an important basis for the development of new strategies targeting the IL-27/Lag3 axis in Tregs to treat MS, and chronic inflammation in other tissues.

Abstract Foxp3+ CD4 T cells (Tregs) play a key role in regulating immunity and tolerance. Defects in Treg generation and/or functions are directly associated with uncontrolled immune activation leading to the development of autoimmune diseases. Yet, the precise mechanisms by which Tregs express the functions remain unclear. Multiple sclerosis (MS) is a myelin antigen specific autoimmune inflammation of the central nervous system (CNS) mediated by myelin antigen specific Th17 type CD4 T cells. Experimental autoimmune encephalomyelitis (EAE) is an animal model that shares clinical and histological features with MS, and is widely used to investigate the pathogenesis as well as to develop an approach to treat the disease. Increasing evidence suggests that Treg function may be dysregulated in MS patients or EAE bearing mice. Thus, identifying pathways that improve Treg function is an issue of clinical importance to develop a potential therapy targeting Tregs. The major goal of this application is to test the role of IL-27 in Treg function. We recently reported that IL-27 signaling in Tregs plays an essential role in suppressing Th17 type inflammation in the intestine. We utilized a newly developed Treg-specific Il27ra-/- animal and found that Treg-specific IL-27R deficiency results in a severe EAE. CNS infiltrating CD4 T cells producing proinflammatory cytokines were uncontrolled in the presence of Il27ra-/- Tregs, while IL-10+ CD4 T cells implicated in regulation of inflammatory responses remained unchanged. Genome wide microarray analysis revealed that IL-27 stimulation in Tregs induces Lag3, a CD4 like molecule implicated in negative regulation of T cell activation. We then used a novel Treg-specific Lag3-/- animal and found that they also develop severe EAE, suggesting that Treg expression of Lag3 may be critical to mediate IL-27-induced Treg function. Finally, IL-27 prestimulation in Tregs significantly enhances suppressive function both in vitro and in vivo. The overall hypothesis is that IL-27 controls Treg suppressive function during EAE and that Lag3 induced by IL-27 signaling plays a key role in mediating IL-27 effect on Tregs. We also propose that the suppressive function of Tregs can be improved by IL-27 prestimulation, reversing ongoing inflammation in the CNS. Three specific aims are proposed. Aim #1 will test the role of IL-27 signaling on Treg function during EAE. Aim #2 will test To test the role of Lag3 during IL-27-mediated control of Treg function. Aim #3 will test the mechanisms by which IL-27 prestimulated Tregs efficiently reverse ongoing neuroinflammation. We anticipate that the results from this study will identify novel mechanisms by which IL-27 modulates Treg function via Lag3 to downregulate inflammation in the CNS. Completing the proposed studies will provide an important basis for the development of new strategies targeting the IL-27/Lag3 axis in Tregs to treat MS, and chronic inflammation in other tissues.

项目成果

Lymphocyte activation gene 3 (Lag3) supports Foxp3 + Treg cell function by restraining c-Myc-dependent aerobic glycolysis.

淋巴细胞激活基因 3 (Lag3) 通过抑制 c-Myc 依赖性有氧糖酵解来支持 Foxp3 Treg 细胞功能。

• DOI: 10.1101/2023.02.13.528371
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Kim,Dongkyun;Kim,Giha;Yu,Rongzhen;Lee,Juyeun;Kim,Sohee;Qiu,Kevin;Montauti,Elena;Fang,Deyu;Chandel,NavdeepS;Choi,Jaehyuk;Min,Booki
• 通讯作者: Min,Booki

Single-Cell Analysis Uncovers Striking Cellular Heterogeneity of Lung-Infiltrating Regulatory T Cells during Eosinophilic versus Neutrophilic Allergic Airway Inflammation.

单细胞分析揭示了嗜酸性粒细胞与中性粒细胞过敏性气道炎症期间肺浸润调节性 T 细胞的惊人细胞异质性。

• DOI: 10.4049/jimmunol.2300646
• 发表时间: 2024
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Iamsawat,Supinya;Yu,Rongzhen;Kim,Sohee;Dvorina,Nina;Qiu,Kevin;Choi,Jaehyuk;Baldwin3rd,WilliamM;Min,Booki
• 通讯作者: Min,Booki

Cell type specific IL-27p28 (IL-30) deletion in mice uncovers an unexpected regulatory function of IL-30 in autoimmune inflammation.

• DOI: 10.1038/s41598-023-27413-w
• 发表时间: 2023-02-01
• 期刊: Scientific reports
• 影响因子: 4.6

Spontaneous T Cell Proliferation: A Physiologic Process to Create and Maintain Homeostatic Balance and Diversity of the Immune System.

• DOI: 10.3389/fimmu.2018.00547
• 发表时间: 2018
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Min B