Tfh cells: linking the gut microbiota to a gut-distal autoimmune disease

Tfh 细胞：将肠道微生物群与肠道远端自身免疫性疾病联系起来

• 批准号: 8696023
• 负责人: Hsin-Jung Joyce Wu
• 金额: $ 20.07万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8696023
• 关键词: Address; Affect; Affinity; Area; Arizona; Arthritis; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; B cell differentiation; B-Lymphocytes; BLR1 gene; Bacteria; Cell Count; Cell Differentiation process; Cell Proliferation; Cells; Data; Defect; Development; Disease; Distal; Germ-Free; Glucosephosphate Isomerase; Helper-Inducer T-Lymphocyte; IgG1; Immune; Immune System Diseases; Immune response; Immunity; Immunization; Immunocompromised Host; Immunoglobulin A; Immunologic Receptors; Individual; Integrins; Interleukin-17; Interleukin-4; Intestines; K/BxN model; Lead; Link; Lupus; Lymphoid Tissue; MHC Class II Genes; Mediating; Medical; Microbe; Modeling; Mus; Pathway interactions; Population; Production; Public Health; Regulatory T-Lymphocyte; Reporting; Role; Serum; Signal Transduction; Site; Specific Pathogen Frees; Spleen; Structure of aggregated lymphoid follicle of small intestine; Structure of germinal center of lymph node; System; T-Cell Receptor; T-Lymphocyte; Testing; Th2 Cells; Transgenic Mice; Universities; Work; autoimmune arthritis; base; cell type; commensal microbes; congenic; cytokine; disease phenotype; germ free condition; gut microbiota; in vivo; novel; overexpression; public health relevance; receptor; response; systemic autoimmune disease

DESCRIPTION (provided by applicant): The gut microbiota has been implicated in many autoimmune diseases, both inside and outside the gut (gut- distal/systemic). However, how gut microbiota affects gut-distal diseases remains largely unknown. Notably, commensals have been reported to affect certain T cell subtype(s) including T helper 1 (Th1), Th17, and regulatory T cells (Tregs), but little is known about how or which commensals impact T follicular helper (Tfh) cells. Tfh cells are a crucial T cell type that helps B cells produce high-affinity antibodie (Abs) in the germinal center (GC). However, an overactive Tfh cell response can lead to autoimmunity. We have established a new and more physiologically relevant platform to study the commensal effect by introducing segmented filamentous bacteria (SFB) into specific-pathogen-free (rather than germ-free, our old approach) K/BxN autoimmune arthritis mice, whose disease mechanism relies on Tfh cells and auto-Abs. Our new data show that SFB strongly enhances disease in K/BxN mice and indicate a role for SFB in Tfh cells, as an increase in the Tfh and GC cell populations was observed in SFB (+) compared to SFB (-) K/BxN mice. To our knowledge, this is the first data to associate a specific commensal type with Tfh cells. Therefore, we hypothesize that gut microbiota can drive gut-distal autoimmune disease by enhancing the Tfh cell response. We will examine: 1) the mechanism for SFB-dependent expansion of systemic (splenic) Tfh cells and their significance in augmenting disease; 2) whether SFB boosts auto-Ab response by inducing Tfh cell cytokines, reprogramming other Th subtypes into Tfh cells, or directly acting on B cells; and 3) whether the gut can serve as a Tfh priming site, which is required for the systemic Tfh cell response. Specifically, we will address if SFB increases the number of Tfh cells by enhancing proliferation, survival, and/or differentiation. We will determine if Tfh cells are critical for SFB-mediated disease by using a K/BxN transfer model with CXCR5-/-KRN T cells, which are defective in mounting a Tfh response. We will use retroviral systems to see if overexpression of SFB- dependent cytokines can correct the defects in SFB (-) Tfh cells. We will test whether SFB can reprogram Th17 and Th2 cells into Tfh cells by adoptively transferring ex-vivo isolated Th17 or Th2 cells. We will use a transfer model with innate signaling-deficient MyD88-/- B cells to test if SFB can help B cells by acting directly on them through innate receptors. Our new data show a tremendous SFB-dependent increase in Tfh cells in the gut Peyer's patch (PP). Thus, we will examine the role of gut T cells in the splenic Tfh response by generating mice that lack T cells in gut-lymphoid-tissue (using transfer model with integrin ¿7-/-KRN T cells). Importantly, our latest data indicate strong significance and broad applications of this proposal, as the Tfh/GC enhancing effect of SFB found in the K/BxN model can also be demonstrated in NZB/NZW F1 mice, a natural and spontaneous lupus model. Studying the commensal effect on Tfh cells will have crucial impacts on public health, as dysbiosis caused by modern medical practice might trigger autoimmunity by affecting Tfh cells.

描述（由申请人提供）：肠道微生物群与肠道内部和外部（肠道远端/全身）的许多自身免疫性疾病有关。然而，肠道微生物群如何影响肠道远端疾病仍然很大程度上未知。值得注意的是，据报道，共生体会影响某些 T 细胞亚型，包括辅助性 T 细胞 1 (Th1)、Th17 和调节性 T 细胞 (Treg)，但人们对共生体如何或哪些共生体影响滤泡辅助 T (Tfh) 细胞知之甚少。 Tfh 细胞是一种重要的 T 细胞类型，可帮助 B 细胞在生发中心 (GC) 产生高亲和力抗体 (Ab)。然而，过度活跃的 Tfh 细胞反应可能导致自身免疫。我们建立了一个新的、更具生理相关性的平台，通过将分段丝状细菌（SFB）引入无特定病原体（而不是无菌，我们的旧方法）K/BxN自身免疫性关节炎小鼠中来研究共生效应，其疾病机制依赖于Tfh细胞和自身抗体。我们的新数据表明，SFB 强烈增强 K/BxN 小鼠的疾病，并表明 SFB 在 Tfh 细胞中的作用，因为与 SFB (-) K/BxN 小鼠相比，在 SFB (+) 中观察到 Tfh 和 GC 细胞群增加。据我们所知，这是第一个将特定共生类型与 Tfh 细胞相关联的数据。因此，我们假设肠道微生物群可以通过增强 Tfh 细胞反应来驱动肠道远端自身免疫性疾病。我们将研究：1）SFB 依赖性全身（脾）Tfh 细胞扩张的机制及其在加重疾病方面的重要性； 2) SFB是否通过诱导Tfh细胞细胞因子、将其他Th亚型重编程为Tfh细胞或直接作用于B细胞来增强自身抗体反应； 3) 肠道是否可以作为 Tfh 启动位点，这是全身 Tfh 细胞反应所必需的。具体来说，我们将讨论 SFB 是否通过增强增殖、存活和/或分化来增加 Tfh 细胞的数量。我们将通过使用具有 CXCR5-/-KRN T 细胞的 K/BxN 转移模型来确定 Tfh 细胞是否对 SFB 介导的疾病至关重要，CXCR5-/-KRN T 细胞在产生 Tfh 反应方面存在缺陷。我们将使用逆转录病毒系统来观察 SFB 依赖性细胞因子的过度表达是否可以纠正 SFB (-) Tfh 细胞的缺陷。我们将测试SFB是否可以通过过继转移离体分离的Th17或Th2细胞将Th17和Th2细胞重编程为Tfh细胞。我们将使用具有先天信号传导缺陷的 MyD88-/- B 细胞的转移模型来测试是否 SFB 可以通过先天受体直接作用于 B 细胞，从而帮助 B 细胞。我们的新数据显示肠道派尔氏淋巴结 (PP) 中 Tfh 细胞依赖于 SFB 的巨大增加。因此，我们将通过培养缺乏 T 细胞的小鼠来检查肠道 T 细胞在脾 Tfh 反应中的作用。 肠-淋巴-组织（使用整合素¿7-/-KRN T 细胞的转移模型）。重要的是，我们的最新数据表明该提议具有很强的意义和广泛的应用，因为在 K/BxN 模型中发现的 SFB 的 Tfh/GC 增强作用也可以在 NZB/NZW F1 小鼠（一种自然自发的狼疮模型）中得到证明。研究 Tfh 细胞的共生效应将对公众健康产生至关重要的影响，因为现代医学实践引起的生态失调可能会通过影响 Tfh 细胞而引发自身免疫。