Origin and Function of Double Negative T cells in Lupus
Origin and Function of Double Negative T cells in Lupus
批准号:
10512753
负责人:
Andre Ballesteros-Tato
金额:
$50.9万
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
未结题
起止时间:
2020-11-19 至 2025-10-31
关键词:
Adoptive TransferApoptosisAutoantibodiesAutoimmuneAutoimmune DiseasesB-LymphocytesCD3 AntigensCD4 Positive T LymphocytesCD8-Positive T-LymphocytesCD8B1 geneCellsChildDataDevelopmentDiseaseDoseEquilibriumFrequenciesGenerationsGenetic DiseasesGenetic TranscriptionGoalsHelper-Inducer T-LymphocyteHeterogeneityHomeostasisHumanHybridsIL17 geneImmunosuppressionImmunotherapyInterleukin-2LupusMediatingMolecularMusPathogenesisPathogenicityPathologyPathway interactionsPatientsPhenotypePlasma CellsPlasma EnhancementPlayPopulationProductionRoleSTAT3 geneSeverity of illnessSignal TransductionSystemic Lupus ErythematosusT cell responseT-Cell DevelopmentT-LymphocyteTestingTherapeuticTherapeutic Interventionautoimmune lymphoproliferative syndromeautoreactivitycytokinedesignexperimental studyin vivoinhibitorlupus prone micenovelnovel therapeutic interventionpreventprogramsresponseself helpsingle-cell RNA sequencingsynergism
中文摘要
总结。B细胞耐受性的丧失和浆细胞(PC)产生自身抗体(Ab)是主要原因
在系统性红斑狼疮(SLE)病理中的作用。尽管抗体依赖的致病机制可以部分地
在免疫抑制的控制下,抗体介导的疾病无法治愈。主要限制之一是
在制定旨在预防抗体依赖病理的治疗策略时,缺乏准确的
了解如何生成和维护自动反应PC。在这方面,T卵泡助手(TFH)
细胞是CD4T细胞的一个亚群,为B细胞提供帮助,在促进自身反应性PC方面发挥着关键作用。
因此,自身反应性TFH细胞的扩张与自身抗体的产生和疾病的严重程度相关
鼠狼疮和人类狼疮。与TFH细胞类似,双阴性(DN)T细胞是一种特殊的T细胞群
以缺乏CD4和CD8表达为特征的,在狼疮中也会扩大。重要的是,
糖尿病肾病T细胞也与疾病活动性和自身抗体的产生有关。因此,人们普遍认为,这些
细胞在自身免疫性疾病的发病机制中起着重要作用。尽管它们在疾病发展中起着推定的作用,但我们
不知道是什么信号控制了糖尿病肾病T细胞的形成,它们的确切来源和致病功能仍然存在
在很大程度上是难以捉摸的。此外,调节糖尿病肾病T细胞稳态的机制是完全未知的,并且
目前还没有在体内选择性地去除糖尿病肾病T细胞的治疗方法。这项提议的主要目标是
明确控制致病性糖尿病肾病T细胞发育和功能的细胞和分子机制。在……里面
在这方面,我们的初步数据表明,DNT细胞和TFH细胞具有共同的表型,转录,
和发展要求。因此,我们已经确定了一组Bcl6dN T细胞
表型与TFH细胞相似。将在该提案中检验的中心假设是TFH细胞是
Bcl6dN T细胞的前体细胞与Tfh细胞相似,是有效的B细胞辅助者。
重要的是,我们的初步数据还表明,Bcl6dN T细胞比Tfh细胞更具可塑性,这
使他们能够获得我们认为对支持自动反应PC至关重要的TFH/Th17混合签名
回应。在目标1中,我们将检验Tfh细胞是Bcl6dN T细胞的前体的假设,并检验
这些细胞帮助自身反应的B细胞的能力。在目标2.1中,我们将测试IL-1的假设
17糖尿病肾病T细胞的产生对于支持PC反应和抗体介导的病理是至关重要的。在AIM 2.2中,我们
将确定控制获得“混合”Tfh/Th17签名的分子机制。最后,在
目的3、我们将开发一种新的以IL-2为基础的协同免疫疗法,旨在选择性地靶向Tfh和
超低剂量rIL-2联合STAT3-2抑制IL-17 Bcl6-dN T细胞分化
信号封锁。我们相信,我们的研究将为研究糖尿病肾病T细胞的致病性提供一个新的范例
将揭示与自身免疫性疾病发病机制有关的新途径,并将对
设计新的治疗干预措施,以靶向TfH和DNT细胞,并防止抗体介导的病理。
英文摘要
SUMMARY. Loss of B cell tolerance and production of auto-antibodies (Ab) by plasma cells (PCs) play a major
role in Systemic Lupus Erythematosus (SLE) pathology. Though Ab-dependent pathogenesis can be partially
controlled with immunosuppression, there is no cure for Ab-mediated disorders. One of the main limitations
when developing therapeutic strategies aimed to prevent Ab-dependent pathology is the lack of a precise
understanding of how auto-reactive PCs are generated and maintained. In this regard, T follicular helper (Tfh)
cells, a subset of CD4+ T cells that provides help to B cells, play a critical role in promoting auto-reactive PCs.
As such, the expansion of self-reactive Tfh cells correlates with auto-Ab production and disease severity in
murine and human lupus. Similar to Tfh cells, Double-negative (DN) T cells, a particular population of T cells
that characteristically lack CD4 and CD8 expression, are also expanded in lupus. Importantly, the frequency of
DN T cells also correlates with disease activity and auto-Ab production. Thus, it is generally believed that these
cells play a role in autoimmune disease pathogenesis. Despite their putative role in disease development, we
do not know what signals control DN T cell formation, and their exact origin and pathogenic function remain
largely elusive. Furthermore, the mechanisms that regulate DN T cell homeostasis are entirely unknown, and
there are currently no therapies to selectively deplete DN T cells in vivo. The main goal of this proposal is to
define the cellular and molecular mechanisms that control pathogenic DN T cell development and function. In
this regard, our preliminary data demonstrate that DN T cells and Tfh cells share phenotypic, transcriptional,
and developmental requirements. As such, we have identified a population of Bcl6+ DN T cells that
phenotypically resemble Tfh cells. The central hypothesis that will be tested in this proposal is that Tfh cells are
the precursors of Bcl6+ DN T cells and that, similar to Tfh cells, these cells are efficient B cell helpers.
Importantly, our preliminary data also suggest that Bcl6+ DN T cells are more plastic than Tfh cells, which
allows them to acquire a “hybrid” Tfh/Th17 signature that we believe is critical for supporting auto-reactive PC
responses. In Aim 1, we will test the hypothesis that Tfh cells are precursors of Bcl6+ DN T cells and examine
the capacity of these cells to help self-reactive B cell responses. In Aim 2.1, we will test the hypothesis that IL-
17 production by DN T cells is critical for supporting PC responses and Ab-mediated pathology. In Aim 2.2, we
will determine the molecular mechanisms controlling the acquisition of a “hybrid” Tfh/Th17 signature. Finally, in
Aim 3, we will develop a new synergistic IL-2-based immunotherapy aimed to selectively target Tfh and
prevent the differentiation of IL-17+Bcl6+DN T cells by combining “ultra-low” doses of rIL-2 with STAT3-
signaling blockade. We believe that our studies will provide a new paradigm for how pathogenic DN T cells are
generated, will reveal new pathways implicated in autoimmune disease pathogenesis, and will be crucial for
designing new therapeutic interventions to target Tfh and DN T cells and prevent Ab-mediated pathology.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Functional Implications of Tfh Cell Heterogeneity after Infection
-
批准号:10442020
-
项目类别:
-
资助金额:$55.5万
-
财政年份:2022
-
负责人:Andre Ballesteros-Tato
-
依托单位:
Functional Implications of Tfh Cell Heterogeneity after Infection
-
批准号:10554312
-
项目类别:
-
资助金额:$55.5万
-
财政年份:2022
-
负责人:Andre Ballesteros-Tato
-
依托单位:
Functional Implications of Tfh Cell Heterogeneity after Infection
-
批准号:10466217
-
项目类别:
-
资助金额:$53.62万
-
财政年份:2021
-
负责人:Andre Ballesteros-Tato
-
依托单位:
Origin and Function of Double Negative T cells in Lupus
-
批准号:10304940
-
项目类别:
-
资助金额:$50.9万
-
财政年份:2020
-
负责人:Andre Ballesteros-Tato
-
依托单位:
Regulation of T-cell dependent B cell responses to influenza
-
批准号:8996709
-
项目类别:
-
资助金额:$36.75万
-
财政年份:2015
-
负责人:Andre Ballesteros-Tato
-
依托单位:
国内基金
海外基金
登录
查看更多内容
Epac1/2通过蛋白酶体调控中性粒细胞NETosis和Apoptosis在急性肺损伤中的作用研究
-
批准号:LBY21H010001
-
项目类别:省市级项目
-
资助金额:--
-
批准年份:2020
-
负责人:郑绪阳
-
依托单位:
基于Apoptosis/Ferroptosis双重激活效应的天然产物AlbiziabiosideA的抗肿瘤作用机制研究及其结构改造
-
批准号:81703335
-
项目类别:青年科学基金项目
-
资助金额:20.0万元
-
批准年份:2017
-
负责人:卫高菲
-
依托单位:
双肝移植后Apoptosis和pyroptosis在移植物萎缩差异中的作用和供受者免疫微环境变化研究
-
批准号:81670594
-
项目类别:面上项目
-
资助金额:58.0万元
-
批准年份:2016
-
负责人:陈昊
-
依托单位:
Serp-2 调控apoptosis和pyroptosis 对肝脏缺血再灌注损伤的保护作用研究
-
批准号:81470791
-
项目类别:面上项目
-
资助金额:73.0万元
-
批准年份:2014
-
负责人:董家鸿
-
依托单位:
Apoptosis signal-regulating kinase 1是七氟烷抑制小胶质细胞活化的关键分子靶点?
-
批准号:81301123
-
项目类别:青年科学基金项目
-
资助金额:23.0万元
-
批准年份:2013
-
负责人:王海莲
-
依托单位:
APO-miR(multi-targeting apoptosis-regulatory miRNA)在前列腺癌中的表达和作用
-
批准号:81101529
-
项目类别:青年科学基金项目
-
资助金额:22.0万元
-
批准年份:2011
-
负责人:陈雪芹
-
依托单位:
放疗与细胞程序性死亡(APOPTOSIS)相关性及其应用研究
-
批准号:39500043
-
项目类别:青年科学基金项目
-
资助金额:9.0万元
-
批准年份:1995
-
负责人:梁克
-
依托单位: