IL-2 Family Cytokines and their Receptors-- Biology of the IL-2 system
IL-2 家族细胞因子及其受体——IL-2 系统的生物学
基本信息
- 批准号:10262667
- 负责人:
- 金额:$ 160.38万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:Adoptive TransferAdult T-Cell Leukemia/LymphomaAffinityAgonistAllergicAntitumor ResponseApoptosisAttenuatedAutoimmune DiseasesB-Cell DevelopmentB-LymphocytesBCL6 geneBindingBiologicalBiological ProcessBiologyCD27 AntigensCD4 Positive T LymphocytesCD8-Positive T-LymphocytesCRISPR/Cas technologyCell Differentiation processCellsCellular immunotherapyChIP-seqChromatinChromatin Interaction Analysis by Paired-End Tag SequencingCitric Acid CycleClosure by clampCoupledCytokine ReceptorsDNA sequencingDataDefectDendritic CellsDevelopmentDiseaseElementsEnhancersEventExperimental Autoimmune EncephalomyelitisFamilyGene ExpressionGenerationsGenesGenetic TranscriptionGenomic approachGranulocyte-Macrophage Colony-Stimulating FactorHaplotypesHelminthsHelper-Inducer T-LymphocyteHeterodimerizationHost DefenseHumanHuman T-lymphotropic virus 1IFNG geneIL2RA geneIL6ST geneIRF4 geneImmune responseImmunologic Deficiency SyndromesImmunologicsIn VitroInbred Strains MiceInflammatoryInflammatory Bowel DiseasesInnate Immune ResponseInterferon Type IInterferonsInterleukin 2 ReceptorInterleukin 2 Receptor GammaInterleukin-15Interleukin-2Interleukin-4Interleukin-7Interleukin-9Lactate DehydrogenaseMalignant - descriptorMalignant NeoplasmsMediatingMemoryMetabolicMetabolismMethodologyMolecularMusMutateNatural Killer CellsNuclear FamilyNuclear ReceptorsOxidative PhosphorylationPRDM1 genePathologicPhenotypePhysiologicalPlayPredispositionProductionProtein FamilyProto-Oncogene Proteins c-junPsoriasisPyruvateReceptor SignalingRegulationReportingRepressionResponse ElementsRoleSTAT proteinSTAT1 geneSTAT3 geneSTAT5B geneSeverity of illnessShapesSignal TransductionStaphylococcus aureusStat5 proteinStructure of germinal center of lymph nodeSystemT cell differentiationT memory cellT-Cell ActivationT-LymphocyteTP53 geneTh1 CellsTherapeuticTimeTranscription Factor AP-1Transgenic MiceVariantVirusX-Linked Severe Combined ImmunodeficiencyXBP1 geneaerobic glycolysisbasecell typechromatin immunoprecipitationcytokinedimerexhaustiongenetic analysisgenome-widegraft vs host diseasehuman diseaseimmune functionimmune system functionin vivoinsightinterestinterleukin-21 receptormRNA Expressionmembermutantneutrophilnext generationnovelpathogenpreventprogramspromoterprotein activationprotein expressionprotein p73receptorresponsestem cellstranscription factortranscriptomicstumor
项目摘要
The IL-2 receptor and related cytokine/cytokine receptor systems are being studied to understand the T cell immune response in normal and pathologic states. After T-cell activation, the magnitude and duration of the response is controlled in part by the amount of IL-2 produced, levels of IL-2 receptors, and the time course of their induction. IL-2Ra expression is highly expressed by cells infected with HTLV-I, the cause of adult T cell leukemia (ATL). There are 3 chains of the receptor: IL-2Ra, IL-2Rb, and gc, with IL-2Ra and IL-2Rb highly regulated at the level of transcription. gc is shared by the IL-4, IL-7, IL-9, IL-15, and IL-21 receptors and is mutated in XSCID. We study the signals induced by these cytokines, particularly STAT proteins and the mechanisms by which they regulate target genes. Our prior data that Stat5a or Stat5b transgenic mice develop tumors are consistent with STAT5 playing a role in malignant transformation and STAT5 is elevated in a range of human tumors. Moreover, humans and mice with altered STAT protein expression or activation have immunological defects.
T helper cell differentiation is critical for normal immune responses, with Th1 differentiation important for host defense to viruses/intracelllular pathogens, Th2 differentiation vital in allergic disorders/helminths, and Th17 differentiation vital in inflammatory disorders, including psoriasis and inflammatory bowel disease. We previously showed that IL-2 is important for Th2 differentiation and that IL-2 induces IL-4R expression in a STAT5-dependent manner and controls priming of cells for Th2 differentiation. Moreover, using genome-wide chromatin immunoprecipitation coupled to DNA sequencing (ChIP-Seq) analysis, we previously found broad regulation of Th2 differentiation via STAT5A and STAT5B and extended these findings by showing that IL-2 via STAT5 induces IL-12Rb2, which is critical for Th1 differentiation. We also showed that IL-2 via STAT5 regulates T-bet. Interestingly, IL-2 also inhibits expression of IL-6Ra and gp130, helping to explain the inhibition of Th17 differentiation. We also previously reported ed a key role of IL-2 in Th9 differentiation, with IL-2 inducing STAT5 binding to the Il9 promoter, and that IL-2 and IL-21 had opposing actions in Th9 differentiation, with BCL6 induction by IL-21 but repression by IL-2. In the current year, we have studied the role of new molecules, identified by a computational genomics approach, in Th differentiation, analyzing in vitro differentiated Th1 cells from 16 inbred mouse strains. Haplotype-based computational genetic analysis implicated the p53 family protein, p73, in Th1 differentiation. In vitro, p73 negatively regulates IFN production. p73 binds within, or upstream of, and modulates the expression of Th1 differentiation-related genes Ifng and Il12rb2. Furthermore, in mouse experimental autoimmune encephalitis, p73-deficient mice had increased IFN production and less disease severity, whereas in adoptive transfer inflammatory bowel disease, transfer of p73-deficient nave CD4+ T cells increases Th1 responses and augments disease severity. We thus identified p73 as a negative regulator of the Th1 immune response, suggesting that p73 dysregulation may contribute to susceptibility to autoimmune disease.
We previously collaborated with Dr. K. Christopher Garcia (Stanford), generating novel IL-2 variants, which represent the first partial agonists for a type 1 cytokine. These next-generation IL-2 variants function as "receptor signaling clamps," retaining high affinity for IL-2Rb but having weaker interaction with gc, thus attenuating IL-2Rb/gc heterodimerization. We previously showed that a variant, H9-RETR, prolonged survival in graft-versus-host disease and blocked proliferation of smoldering adult T cell leukemia (ATL) T cells. During the past year, we continued our study of these molecules and additionally have studied a new IL-2 partial agonist.
IL-21 has broad actions on T- and B-cells, and we previously reported that it induces apoptosis of conventional dendritic cells via STAT3 and Bim, and that this is inhibited by GM-CSF. ChIP-Seq analysis had revealed genome-wide binding competition between GM-CSF-induced STAT5 and IL-21-induced STAT3, and we had elucidated roles for STAT1 vs. STAT3 in IL-21 signaling in T cells. We had also demonstrated that IL-21 regulates expression of the Prdm1 gene (encoding BLIMP1) via a response element that depends on STAT3 and IRF4 and found that in contrast to its known ability to cooperate with PU.1 in B cells to act via Ets-IRF composite elements, IRF4 cooperates with BATF/JUN family proteins to act via novel AP1-IRF composite elements (AICEs) in T cells, as well as in B cells. In the previous year, we extended our studies with H.C. Morse, reporting that the transcription factors IRF8 and PU.1 are required for follicular B cell development and BCL6-driven germinal center responses. We also had reported a role for IL-21 in neutrophil biology and shown its cooperative interplay with type I interferon in regulating the innate immune response to S. aureus. In the current year, we elucidated mechanisms underlying actions of IL-2 versus IL-21, reporting that they dichotomously shape CD8+ T cell differentiation. IL-2 drives terminal differentiation, generating cells that are poorly effective against tumors, whereas IL-21 promotes stem cell memory T cells (TSCM) and antitumor responses. IL-2 promoted effector-like metabolism and aerobic glycolysis, robustly inducing lactate dehydrogenase (LDH) and lactate production, whereas IL-21 maintained a metabolically quiescent state dependent on oxidative phosphorylation. LDH inhibition rewired IL-2-induced effects, promoting pyruvate entry into the tricarboxylic acid cycle and inhibiting terminal effector and exhaustion programs, including mRNA expression of members of the NR4A family of nuclear receptors, as well as Prdm1 and Xbp1. Deletion of Ldha prevented development of cells with antitumor effector function, but transient LDH inhibition enhanced the generation of memory cells that could trigger robust antitumor responses after adoptive transfer. LDH inhibition caused major transcriptomic changes, and LDH inhibition combined with IL-21 increased the formation of TSCM cells, resulting in more profound antitumor responses and prolonged host survival. These findings indicate a pivotal role for LDH in modulating cytokine-mediated T cell differentiation and underscore the therapeutic potential of transiently inhibiting LDH during adoptive T cell-based immunotherapy.
Previously, we studied the biological significance of STAT5 tetramerization in vivo by generating mice expressing mutant forms of STAT5A and STAT5B that could form dimers but not tetramers, and we also previously reported a critical role for STAT5 tetramers for the survival of NK cells. In the current year, we now have extended our studies of tetramers within other cell types as well. We also previously globally characterized super-enhancers regulated by IL-2-activated STAT5 and IL-21-activated STAT3 and their relationship to highly inducible genes and had found that the Il2ra gene contains the most highly ranked STAT5-dependent super enhancer. Using ChIA-PET methodology, we had defined long-distance chromatin interactions and used CRISPR-Cas9 technology to functionally dissect elements of this super-enhancer, providing new insights into the molecular regulation of the Il2ra in particular and super-enhancers in general. In the current year, we have significantly extended these studies.
Overall, these studies enhance our understanding of the mechanism by which gc family cytokines regulate gene expression/biological processes and are relevant to normal and pathological immune function.
人们正在研究IL-2受体和相关的细胞因子/细胞因子受体系统,以了解T细胞在正常和病理状态下的免疫反应。在t细胞激活后,反应的大小和持续时间部分由产生的IL-2的数量、IL-2受体的水平和它们诱导的时间过程控制。IL-2Ra的表达在感染HTLV-I(成人T细胞白血病(ATL)的病因)的细胞中高度表达。受体有IL-2Ra、IL-2Rb和gc 3条链,IL-2Ra和IL-2Rb在转录水平上受到高度调控。gc由IL-4、IL-7、IL-9、IL-15和IL-21受体共享,在XSCID中发生突变。我们研究了这些细胞因子,特别是STAT蛋白诱导的信号及其调节靶基因的机制。我们之前的数据表明Stat5a或Stat5b转基因小鼠会发生肿瘤,这与STAT5在恶性转化中发挥作用是一致的,STAT5在一系列人类肿瘤中升高。此外,STAT蛋白表达或激活改变的人和小鼠具有免疫缺陷。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Warren J Leonard其他文献
The role of Stat5a and Stat5b in signaling by IL-2 family cytokines
Stat5a 和 Stat5b 在白细胞介素 2 家族细胞因子信号传导中的作用
- DOI:
10.1038/sj.onc.1203523 - 发表时间:
2000-05-25 - 期刊:
- 影响因子:7.300
- 作者:
Jian-Xin Lin;Warren J Leonard - 通讯作者:
Warren J Leonard
Priming for T helper type 2 differentiation by interleukin 2–mediated induction of interleukin 4 receptor α-chain expression
白细胞介素 2 介导的白细胞介素 4 受体α链表达诱导对 T 辅助 2 型分化的启动
- DOI:
10.1038/ni.1656 - 发表时间:
2008-09-28 - 期刊:
- 影响因子:27.600
- 作者:
Wei Liao;Dustin E Schones;Jangsuk Oh;Yongzhi Cui;Kairong Cui;Tae-Young Roh;Keji Zhao;Warren J Leonard - 通讯作者:
Warren J Leonard
JAK3 inhibition—is it sufficient?
JAK3 抑制——这就足够了吗?
- DOI:
10.1038/nchembio.2066 - 发表时间:
2016-04-19 - 期刊:
- 影响因子:13.700
- 作者:
Warren J Leonard;Suman Mitra;Jian-Xin Lin - 通讯作者:
Jian-Xin Lin
Warren J Leonard的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Warren J Leonard', 18)}}的其他基金
IL-2 Family Cytokines and Receptors-- Mechanisms of Regulation & Action
IL-2 家族细胞因子和受体——调节机制
- 批准号:
8746596 - 财政年份:
- 资助金额:
$ 160.38万 - 项目类别:
IL-2 Family Cytokines and their Receptors-- Biology of the IL-21 system
IL-2 家族细胞因子及其受体——IL-21 系统的生物学
- 批准号:
8939804 - 财政年份:
- 资助金额:
$ 160.38万 - 项目类别:
IL-2 Family Cytokines and their Receptors-- Biology of the IL-21 system
IL-2 家族细胞因子及其受体——IL-21 系统的生物学
- 批准号:
8344812 - 财政年份:
- 资助金额:
$ 160.38万 - 项目类别:
IL-2 Family Cytokines and Receptors-- Mechanisms of Regulation & Action
IL-2 家族细胞因子和受体——调节机制
- 批准号:
10262668 - 财政年份:
- 资助金额:
$ 160.38万 - 项目类别:
IL-2 Family Cytokines and their Receptors-- Molecular Regulation via GABP
IL-2 家族细胞因子及其受体——通过 GABP 进行分子调控
- 批准号:
7735035 - 财政年份:
- 资助金额:
$ 160.38万 - 项目类别:
相似海外基金
Pathophysiology of Adult T-cell leukemia/lymphoma
成人 T 细胞白血病/淋巴瘤的病理生理学
- 批准号:
10609828 - 财政年份:2022
- 资助金额:
$ 160.38万 - 项目类别:
Inhibition of T-cell Receptor Signaling for Treatment of Adult T-cell Leukemia Lymphoma
抑制 T 细胞受体信号转导治疗成人 T 细胞白血病淋巴瘤
- 批准号:
10684172 - 财政年份:2022
- 资助金额:
$ 160.38万 - 项目类别:
Pathophysiology of Adult T-cell leukemia/lymphoma
成人 T 细胞白血病/淋巴瘤的病理生理学
- 批准号:
10369933 - 财政年份:2022
- 资助金额:
$ 160.38万 - 项目类别:
Inhibition of T-cell Receptor Signaling for Treatment of Adult T-cell Leukemia Lymphoma
抑制 T 细胞受体信号转导治疗成人 T 细胞白血病淋巴瘤
- 批准号:
10518751 - 财政年份:2022
- 资助金额:
$ 160.38万 - 项目类别:
Adoptive immunotherapy for adult T-cell leukemia/lymphoma with ex vivo expanded multi-tumor associated antigen specific cytotoxic T-cells
使用离体扩增的多肿瘤相关抗原特异性细胞毒性 T 细胞对成人 T 细胞白血病/淋巴瘤进行过继免疫治疗
- 批准号:
20K17375 - 财政年份:2020
- 资助金额:
$ 160.38万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Establishment of a novel drug discovery platform for adult T-cell leukemia/lymphoma using PROTAC technology
利用PROTAC技术建立成人T细胞白血病/淋巴瘤新药发现平台
- 批准号:
20K08736 - 财政年份:2020
- 资助金额:
$ 160.38万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Development of a multiplex RT-PCR method to assess the risk of stage progression in adult T-cell leukemia/lymphoma
开发多重 RT-PCR 方法来评估成人 T 细胞白血病/淋巴瘤分期进展的风险
- 批准号:
20K07700 - 财政年份:2020
- 资助金额:
$ 160.38万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Elucidation of genomic alterations and the clinicopathological significance in adult T-cell leukemia/lymphoma
阐明成人 T 细胞白血病/淋巴瘤的基因组改变及其临床病理学意义
- 批准号:
20K16177 - 财政年份:2020
- 资助金额:
$ 160.38万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Screening of Promising Chemotherapeutic Candidates from Plants against Human Adult T-Cell Leukemia/Lymphoma
从植物中筛选有前途的抗成人 T 细胞白血病/淋巴瘤的化疗候选药物
- 批准号:
19K16403 - 财政年份:2019
- 资助金额:
$ 160.38万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
A new diagnostic algorithm using biopsy specimens in adult T-cell leukemia/lymphoma: combination of RNA in situ hybridization and quantitative PCR for HTLV-1
使用成人 T 细胞白血病/淋巴瘤活检标本的新诊断算法:结合 RNA 原位杂交和 HTLV-1 定量 PCR
- 批准号:
19K07438 - 财政年份:2019
- 资助金额:
$ 160.38万 - 项目类别:
Grant-in-Aid for Scientific Research (C)