Origin and Function of Double Negative T cells in Lupus

狼疮双阴性 T 细胞的起源和功能

• 批准号: 10304940
• 负责人: Andre Ballesteros-Tato
• 金额: $ 50.9万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-11-19 至 2025-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10304940
• 关键词: Adoptive Transfer; Apoptosis; Autoantibodies; Autoimmune; Autoimmune Diseases; B-Lymphocytes; CD3 Antigens; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Characteristics; Child; Data; Development; Disease; Dose; Equilibrium; Frequencies; Generations; Genetic Diseases; Genetic Transcription; Goals; Helper-Inducer T-Lymphocyte; Heterogeneity; Homeostasis; Human; Hybrids; Immunosuppression; Immunotherapy; Interleukin-17; Interleukin-2; Lupus; Mediating; Molecular; Mus; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patients; Phenotype; Plasma Cells; Plasma Enhancement; Play; Population; Production; Role; STAT3 gene; Severity of illness; Signal Transduction; Systemic Lupus Erythematosus; T cell response; T-Cell Development; T-Lymphocyte; Testing; Therapeutic; Therapeutic Intervention; alpha-beta T-Cell Receptor; autoimmune lymphoproliferative syndrome; autoreactivity; base; cytokine; design; experimental study; in vivo; inhibitor; lupus prone mice; novel; novel therapeutic intervention; prevent; programs; response; self help; single-cell RNA sequencing; synergism

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.

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，我们已经鉴定了Bcl 6 + DN T细胞群， 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。