The role of IL-27 signaling in the accumulation and sustained effector function of autoreactive CD8 T cells in type 1 diabetes
The role of IL-27 signaling in the accumulation and sustained effector function of autoreactive CD8 T cells in type 1 diabetes
批准号:
9886072
负责人:
Ashley Ciecko
金额:
$3.71万
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-03-01 至 2020-10-29
关键词:
AffectAntigen-Presenting CellsAutoimmune DiseasesBeta CellBone MarrowCD4 Positive T LymphocytesCD8-Positive T-LymphocytesCandidate Disease GeneCell physiologyChimera organismChromosome 16ComplexDataDendritic CellsDevelopmentDiabetes MellitusDiseaseDisease susceptibilityEffector CellEnvironmentEnvironmental Risk FactorFellowshipFlow CytometryFrequenciesGenesGeneticGenetic Predisposition to DiseaseGoalsHeterogeneityHomingHumanHuman GenomeIL27RA geneImpairmentIn VitroInbred NOD MiceIncidenceInflammatoryInsulinInsulin-Dependent Diabetes MellitusInterleukinsIslets of LangerhansKnowledgeLeadLinkMeasuresMediatingMissionModelingMolecularMusMyelogenousNational Institute of Diabetes and Digestive and Kidney DiseasesNon obesePathogenesisPathogenicityPhenotypePlayPredispositionPreventionProcessProductionQuantitative Trait LociRag1 MouseResearch PersonnelRoleSignal PathwaySignal TransductionStructureStructure of beta Cell of isletSystemT-Cell ActivationT-Cell ReceptorT-LymphocyteT-Lymphocyte SubsetsTestingTransgenic OrganismsWorkautoreactive B cellautoreactivitycareercell injurychronic autoimmune diseasecytokinediabetes pathogenesisdiabeticdiabetogenicexperimental studygenome wide association studyin vivoisletmacrophagenew therapeutic targetpathogenprogramssingle-cell RNA sequencing
中文摘要
项目摘要
I型糖尿病(T1D)是一种慢性自身免疫性疾病,T细胞破坏产生胰岛素的胰腺β
细胞。T1D是遗传易感性和环境因素复杂交互作用的结果。
完全确定导致疾病易感性的遗传和环境因素对于
寻找治疗和预防T1D的成功疗法。人类IL27(编码人类白细胞介素27的亚基
细胞因子白介素27(IL-27)是一种T1D候选基因,位于16号染色体的易感区域。
IL-27在T1D发病机制中的作用尚不清楚。该项目的长期目标是定义
IL-27在T1D发病过程中的作用CD8T细胞是介导β细胞损伤的主要效应者,但它们需要
来自CD4T细胞的帮助。之前对人类和小鼠的研究表明,IL-27信号可以
调节T细胞功能。我们的实验室已经培育出IL-27或IL-27缺乏的非肥胖糖尿病(NOD)小鼠
受体(IL-27Ra),并证明了在CD_4和CD_8 T细胞中IL-27信号转导在
糖尿病的发展。此外,我们的初步数据显示,缺乏直接的IL-27信号导致
降低胰岛CD8T细胞的频率、增殖和细胞因子的产生。把这些放在一起
观察结果使我们假设,IL-27信号对血液中IL-27的积累和持续
自身反应性CD8 T细胞的效应功能。在目标1中,我们将确定IL-27
信号转导直接促进自身反应性CD8T的蓄积和持续效应功能
细胞。这些实验将测试IL-27信号对CD8 T细胞归巢和分化的内在影响
转化为致病效应器。在目标2中,我们将确定引导IL-27信号的机制
促进CD4T细胞帮助自身反应CD8T细胞的能力。致病CD8 T细胞需要帮助
从CD4T细胞中进行激活和繁殖。因此,这些实验将测试CD4T细胞-
内源性IL-27信号对胰岛CD8 T细胞分化的影响这项提议将会取得进展
自身反应性CD8 T细胞分化及其效应功能的认识
T1D。这与NIDDK的使命是一致的,因为该项目的结果可能导致确定
IL-27信号通路作为治疗或预防T1D的新靶点
英文摘要
Project Summary
Type I diabetes (T1D) is a chronic autoimmune disease in which T cells destroy insulin-producing pancreatic β
cells. T1D results from a complex interaction between genetic predisposition and environmental factors.
Completely defining the genetic and environmental factors that contribute to disease susceptibility is crucial to
finding successful therapies in the treatment and prevention of T1D. Human IL27 (encodes a subunit of the
cytokine interleukin (IL)-27) is a T1D candidate gene located in a susceptibility region on chromosome 16. The
function of IL-27 in T1D pathogenesis is unknown. The long-term goal of this project is to define the role of
IL-27 in the progression of T1D. CD8 T cells are the main effectors mediating β cell damage but they require
help from CD4 T cells. Previous studies with both human and mouse have shown that IL-27 signaling can
regulate T cell function. Our lab has generated non-obese diabetic (NOD) mice deficient in IL-27 or IL-27
receptor (IL-27Ra) and demonstrated that IL-27 signaling in both CD4 and CD8 T cells is important for
diabetes development. Additionally, our preliminary data show that lack of direct IL-27 signaling results in
decreased CD8 T cell frequency, proliferation, and cytokine production in the pancreatic islets. Together these
observations lead us to hypothesize that IL-27 signaling is important for the accumulation and sustained
effector function of autoreactive CD8 T cells. In Aim 1, we will determine the mechanism by which IL-27
signaling directly promotes the accumulation and sustained effector function of autoreactive CD8 T
cells. These experiments will test the intrinsic effect of IL-27 signaling on CD8 T cell homing and differentiation
into pathogenic effectors. In Aim 2, we will determine the mechanism by which direct IL-27 signaling
promotes the ability of CD4 T cells to help autoreactive CD8 T cells. Pathogenic CD8 T cells require help
from CD4 T cells for activation and propagation. Therefore, these experiments will test the effect of CD4 T cell-
intrinsic IL-27 signaling on the differentiation of CD8 T cells in the pancreatic islets. This proposal will advance
our understanding of the differentiation and effector function of autoreactive CD8 T cells during the progression
of T1D. This is in line with the mission of NIDDK, as the results of this project could lead to identification of the
IL-27 signaling pathway as a novel therapeutic target for the treatment or prevention of T1D.
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会议论文
The role of IL-27 signaling in the accumulation and sustained effector function of autoreactive CD8 T cells in type 1 diabetes
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批准号:9757557
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项目类别:
-
资助金额:$4.5万
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财政年份:2019
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负责人:Ashley Ciecko
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依托单位:
海外基金