Coordination of T cell-derived signals in intestinal epithelial barrier defense
肠上皮屏障防御中 T 细胞衍生信号的协调
基本信息
- 批准号:10605830
- 负责人:
- 金额:$ 4.13万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-03-01 至 2026-08-31
- 项目状态:未结题
- 来源:
- 关键词:Adoptive TransferAffectAntigen PresentationAutomobile DrivingCD4 Positive T LymphocytesCell CommunicationCellsCessation of lifeChargeChildCitrobacter rodentiumCollaborationsColonComplexCytoprotectionDeveloping CountriesDiarrheaDiseaseEngineeringEnterocytesEpithelial CellsEpitheliumEscherichia coli EHECEscherichia coli InfectionsEtiologyFamilyGenesGenetic TranscriptionGoalsGoblet CellsHost DefenseHyperplasiaImmuneImmune responseImmunologyIn SituInfantInfectionInfectious colitisInflammation MediatorsInflammatory Bowel DiseasesInnovative TherapyIntestinesKnowledgeLGR5 geneLeadLigandsLymphocytic choriomeningitis virusMHC Class II GenesMaintenanceMediatingMetabolicModelingMolecularMucous MembraneMucous body substanceMusOrangesPhasePredispositionPreventionProcessProteinsReportingResearchRoleSTAT3 geneSignal TransductionSurfaceT cell regulationT cell responseT cell therapyT-LymphocyteTCR ActivationTestingTherapeuticTrainingTransgenic OrganismsUp-Regulationantigen-specific T cellsantimicrobialantimicrobial peptidebasecell motilitycell typechemokinecolonic cryptcytokinediarrheal diseaseeffector T cellenteric infectionenteric pathogenenteropathogenic Escherichia colihuman modelinnovationinsightinterleukin-22intestinal barrierintestinal cryptintestinal epitheliummortalitynew therapeutic targetnovelnovel therapeuticspathogenprogramsreceptorrecruitresponserestraintsingle-cell RNA sequencingstem cells
项目摘要
PROJECT SUMMARY
Although much progress has been made in the treatment and prevention of diarrheal illness over the last century,
the developing world is still plagued by diarrheal pathogens, with young children being particularly susceptible
to diarrhea-related deaths. The long-term goal is to better understand how the coordinated responses of both
immune and non-immune cells contribute to intestinal barrier protection during enteric infection. Our group
recently discovered that Th17/22 cells are uniquely charged with protection of the intestinal crypts from enteric
pathogens; however, the mechanisms by which these T cells are recruited to and sustain activation of crypt
intestinal epithelial cells (cIECs) are unknown. The overall objectives in this application are to (i) elucidate the
molecular mechanisms involved in recruiting T cells to cIECs and (ii) determine how recruited T cells interact
with cIECs to deliver protective IL-22 signals. The central hypothesis is that IFN–induced upregulation of IEC-
derived T cell-recruiting chemokines and MHCII expression promotes T cell recruitment to colonic crypts and
targets pathogen-specific T cell-derived IL-22 signals to cIECs, respectively. The rationale for this project is that
molecules involved in both recruitment and localized delivery of IL-22 to IECs will likely yield novel targets for
therapies in diarrheal illnesses and inflammatory bowel disease (IBD), since responses to enteric pathogens and
etiology of IBD share overlapping immune mechanisms. The central hypothesis will be tested by pursuing two
specific aims: 1) IFN signaling in Lgr5+ IECs is critical for recruiting host-protective Cxcr3+ Th1 and Th17/22
cells to the colonic crypts; and 2) pathogen-specific T cells protect intestinal crypts via MHCII-dependent,
sustained IL-22 delivery to IECs. The Citrobacter rodentium (C.r) model of infectious colitis, which closely models
human E. coli infections, will be used to test both aims in this proposal. In Aim I, mice with deletion of the IFNR1
in Lgr5+ IECs will be used to to test the hypothesis that IFN signaling in Lgr5+ IECs is required for upregulation
of T cell-recruiting chemokines Cxcl9 and Cxcl10 and adoptive transfer of Cxcr3-deficient T cells will be used to
determine if the Cxcl9/10-Cxcr3 axis is involved in recruiting CD4+ T cells to cIECs. In Aim II, mice deficient for
MHCII expression on IECs will be utilized to test the requirement of antigen presentation by IECs for IL-22-
mediated protection of the intestinal crypts. In addition, mice that report TCR stimulation and adoptive transfer
of C.r-specific T cells will be used to test the hypothesis that antigen-specific T cell–IEC interactions are important
for protection from C.r infection. The research proposed in this application is innovative because it utilizes a
newly engineered C.r strain to track antigen-specific T cells in the colon, and it offers unique insights into
previously unrecognized roles of Lgr5+ intestinal stem cells. The proposed research is significant because it is
expected to provide novel mechanisms by which T cells and IECs cooperate to protect the host from enteric
pathogens. Ultimately, such knowledge has the potential for innovative therapies for infectious colitis and IBD.
项目概要
尽管上个世纪在腹泻疾病的治疗和预防方面取得了很大进展,
发展中国家仍然受到腹泻病原体的困扰,幼儿尤其容易受到影响
长期目标是更好地了解两者如何协调应对。
免疫和非免疫细胞有助于肠道感染期间的肠道屏障保护。
最近发现 Th17/22 细胞具有独特的功能,可以保护肠隐窝免受肠道侵害
然而,这些 T 细胞被募集到隐窝并维持其激活的机制
肠上皮细胞(cIEC)未知。本申请的总体目标是(i)阐明。
涉及将 T 细胞募集到 cIEC 的分子机制以及 (ii) 确定募集的 T 细胞如何相互作用
与 cIEC 传递保护性 IL-22 信号的中心假设是 IFN-诱导 IEC-的上调。
衍生的 T 细胞募集趋化因子和 MHCII 表达促进 T 细胞募集到结肠隐窝,
分别将病原体特异性 T 细胞衍生的 IL-22 信号靶向 cIEC。
参与 IL-22 招募和局部递送至 IEC 的分子可能会产生新的靶标
腹泻病和炎症性肠病(IBD)的治疗,因为对肠道病原体的反应和
IBD 的病因学具有重叠的免疫机制,将通过两种方法来检验中心假设。
具体目标:1) Lgr5+ IEC 中的 IFNα 信号对于招募宿主保护性 Cxcr3+ Th1 和 Th17/22 至关重要
细胞到结肠隐窝;2) 病原体特异性 T 细胞通过 MHCII 依赖性保护肠隐窝,
传染性结肠炎的啮齿类柠檬酸杆菌 (C.r) 模型持续递送 IL-22,该模型与模型密切相关。
人类大肠杆菌感染,将用于测试本提案中的两个目标,在目标 I 中,使用 IFN-R1 缺失的小鼠。
Lgr5+ IEC 中的 IFN-信号传导是上调所必需的假设
T 细胞募集趋化因子 Cxcl9 和 Cxcl10 以及 Cxcr3 缺陷 T 细胞的过继转移将用于
确定 Cxcl9/10-Cxcr3 轴是否参与将 CD4+ T 细胞募集到 cIEC。
IEC 上的 MHCII 表达将用于测试 IEC 对 IL-22 抗原呈递的要求
此外,报告 TCR 刺激和过继转移的小鼠。
C.r 特异性 T 细胞将用于检验抗原特异性 T 细胞与 IEC 相互作用很重要的假设
为了防止 C.r 感染,本申请中提出的研究具有创新性,因为它利用了
新设计的 C.r 菌株可追踪结肠中的抗原特异性 T 细胞,它提供了独特的见解
Lgr5+肠道干细胞以前未被认识到的作用,这项研究具有重要意义,因为它是
有望提供 T 细胞和 IEC 合作保护宿主免受肠道感染的新机制
最终,这些知识有可能成为感染性结肠炎和炎症性肠病的创新疗法。
项目成果
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