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
摘要B细胞耐受性的丧失和浆细胞(PC)产生自身抗体(Ab)是主要的
在系统性红斑狼疮(SLE)病理学中的作用。尽管Ab依赖性发病机制可以部分地
用免疫抑制剂控制,Ab介导的疾病无法治愈。一个主要的限制
当开发旨在预防Ab依赖性病理学的治疗策略时,
了解如何生成和维护自动反应PC。在这方面,T滤泡辅助细胞(Tfh)
T细胞是为B细胞提供帮助的CD 4 + T细胞的亚群,在促进自身反应性PC中起关键作用。
因此,自身反应性Tfh细胞的扩增与自身抗体产生和疾病严重程度相关,
鼠和人狼疮。与Tfh细胞类似,双阴性(DN)T细胞,一种特殊的T细胞群
特征性地缺乏CD 4和CD 8表达,也在狼疮中扩增。重要的是,
DN T细胞也与疾病活动和自身抗体产生相关。因此,人们普遍认为,
细胞在自身免疫性疾病发病机制中起作用。尽管它们在疾病发展中的假定作用,我们
我不知道是什么信号控制DN T细胞的形成,它们的确切起源和致病功能仍然存在
很难捉摸此外,调节DN T细胞稳态的机制完全未知,
目前还没有选择性地在体内耗尽DNT细胞的疗法。该提案的主要目标是
定义控制致病性DN T细胞发育和功能的细胞和分子机制。在
关于这一点,我们的初步数据表明DN T细胞和Tfh细胞共享表型,转录,
和发展要求。因此,我们已经鉴定出一群Bcl 6 + DN T细胞,
表型类似于Tfh细胞。在本提案中将检验的中心假设是,Tfh细胞是
Bcl 6 + DN T细胞的前体,并且类似于Tfh细胞,这些细胞是有效的B细胞辅助细胞。
重要的是,我们的初步数据还表明,Bcl 6 + DN T细胞比Tfh细胞更具可塑性,
使他们能够获得“混合”Tfh/Th 17签名,我们认为这对支持自反应PC至关重要。
应答在目的1中,我们将检验Tfh细胞是Bcl 6 + DN T细胞的前体的假设,并检查
这些细胞帮助自身反应性B细胞应答的能力。在目标2.1中,我们将检验IL-1的假设。
DN T细胞的17产生对于支持PC应答和Ab介导的病理是至关重要的。在目标2.2中,我们
将确定控制“杂合”Tfh/Th 17特征获得的分子机制。最后在
目的3,我们将开发一种新的基于IL-2的协同免疫疗法,旨在选择性靶向Tfh,
通过将“超低”剂量的rIL-2与STAT 3 - 3组合来防止IL-17+ Bcl 6 +DN T细胞的分化,
信号封锁我们相信,我们的研究将提供一个新的范例,致病性DN T细胞是如何
产生的,将揭示新的途径,涉及自身免疫性疾病的发病机制,并将是至关重要的,
设计新的治疗干预措施,以靶向Tfh和DN T细胞并预防Ab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.
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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
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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:
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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
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批准号:8996709
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项目类别:
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资助金额:$36.75万
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财政年份:2015
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负责人:Andre Ballesteros-Tato
-
依托单位:
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