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: 8707090
• 负责人: Hsin-Jung Joyce Wu
• 金额: $ 35.6万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8707090
• 关键词: Adoptive Transfer; Affect; Affinity; Animals; Antigens; Apoptosis; Area; Autoantibodies; Autoimmune Diseases; Autoimmune Responses; Autoimmunity; B-Lymphocytes; Bacteria; Cell Differentiation process; Cell Proliferation; Cells; Data; Defect; Development; Disease; Dissection; Distal; Foundations; Germ-Free; Gut associated lymphoid tissue; Helper-Inducer T-Lymphocyte; Immune; Immune System Diseases; Immune response; Immunity; Immunization; In Vitro; Individual; Interleukin-17; Interleukin-4; Interleukins; Intestines; K/BxN model; Lead; Link; Lymphoid Tissue; Mediating; Medical; Microbe; Modeling; Mus; Pathogenesis; Pathway interactions; Population; Process; Production; Public Health; Regulatory T-Lymphocyte; Reporting; Role; 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; autoimmune arthritis; base; cell type; commensal microbes; cytokine; disease phenotype; germ free condition; gut microbiota; in vivo; insight; interleukin-21; novel; overexpression; response; systemic autoimmune disease; trend

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 bacteria that reside in the gut affect the gut-distal diseases remains largely unknown. Significant insights have been gained from studying the interactions of several specific commensals, including segmented filamentous bacteria (SFB), and the host. These commensals can affect certain T cell subtype(s) including T helper 1 (Th1), Th17, and regulatory T cells (Tregs). However, almost nothing 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 SFB into specific-pathogen-free (SPF) (rather than germ-free, our old approach) K/BxN autoimmune arthritis mice, whose disease mechanism relies on Tfh cells and auto-Abs. As in GF mice, SFB strongly enhances disease and auto-Ab production in SPF K/BxN mice. Notably, our preliminary data 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 showing an association of a specific commensal type to Tfh cells. Therefore, we hypothesize that gut microbiota can drive gut-distal autoimmune disease by enhancing the Tfh cell response. We will: 1) assess the mechanism for SFB- dependent expansion of systemic Tfh cells; 2) test whether SFB increases auto-Ab production by inducing Tfh cell cytokines or reprogramming other Th subtypes into Tfh cells; and 3) assess whether the gut can serve as a Tfh priming site, which is required for the systemic (splenic) Tfh cell response. We will determine whether SFB increases Tfh cells by enhancing proliferation, survival, and/or differentiation. We will use retroviral systems to see if overexpression of SFB-dependent cytokines can correct the defects of auto-Ab induction in SFB (-) K/BxN Tfh cells. We will also test whether SFB enhances auto-Ab production by increasing Tfh cells through reprogramming of other Th subtypes (in vitro skewed or ex-vivo isolated). Our new data show a tremendous SFB-dependent increase in Tfh cells in the gut Peyer's patch (PP). We expect to see the PP Tfh response occur earlier than the splenic Tfh response, suggesting that the gut, rather than the spleen, is the Tfh priming site. We will examine the role of gut Tfh cells in the splenic Tfh response by generating K/BxN mice that are gut-lymphoid-tissue deficient. We anticipate that SFB will no longer enhance the splenic Tfh response in K/BxN mice with a gut Tfh deficiency. 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. This proposal will help us understand the pathogenesis of autoimmunity and provide new foundations for novel therapies.!

描述(由申请人提供)：肠道微生物区系与许多自身免疫性疾病有关，包括肠道内外(肠道-远端/全身)。然而，寄生在肠道中的细菌如何影响肠道末端疾病在很大程度上仍不清楚。意义重大 通过研究几种特定共生体的相互作用，包括分段丝状细菌(SFB)和宿主，已经获得了一些见解。这些共性可以影响某些T细胞亚型(S)，包括辅助性T细胞1(Th1)、辅助性T细胞17和调节性T细胞(Treg)。然而，关于共生体如何或哪些影响T滤泡辅助(TFH)细胞，几乎一无所知。TFH细胞是一种重要的T细胞类型，帮助B细胞在生发中心(GC)产生高亲和力抗体(Abs)。然而，过度活跃的TFH细胞反应可能导致自身免疫。我们已经建立了一个新的更具生理学相关性的平台来研究共生效应，将SFB引入无特定病原体(SPF)(而不是我们的旧方法)K/BxN自身免疫性关节炎小鼠，其疾病机制依赖于Tfh细胞和自身抗体。与在GF小鼠中一样，SFB强烈促进SPF K/BxN小鼠的疾病和自身抗体的产生。值得注意的是，我们的初步数据表明SFB在Tfh细胞中发挥了作用，因为与SFB(-)K/BxN小鼠相比，在SFB(+)中观察到Tfh和GC细胞群的增加。据我们所知，这是第一个显示特定共生类型与TFH细胞相关的数据。因此，我们假设肠道微生物区系可以通过增强TFH细胞的反应来驱动肠道末端的自身免疫性疾病。我们将：1)评估依赖SFB的全身TFH细胞扩增的机制；2)测试SFB是否通过诱导TFH细胞因子或将其他Th亚型重新编程为TFH细胞而增加自身抗体的产生；以及3)评估肠道是否可以作为TFH的启动部位，这是全身(脾)TFH细胞反应所必需的。我们将确定SFB是否通过促进增殖、存活和/或分化来增加TFH细胞。我们将使用逆转录病毒系统来观察 在SFB(-)K/BxN Tfh细胞中过表达sFB依赖的细胞因子可纠正自身抗体诱导缺陷。我们还将测试SFB是否通过重新编程其他Th亚型(体外倾斜或体外分离)来增加Tfh细胞，从而提高自身抗体的产生。我们的新数据显示，肠道Peyer氏斑(PP)中TFH细胞的数量显著增加，这是SFB的依赖。我们期望看到PP TFH反应比脾TFH反应发生得更早，这表明肠道而不是脾是TFH的启动部位。我们将通过产生肠道淋巴组织缺陷的K/BxN小鼠来研究肠道Tfh细胞在脾Tfh反应中的作用。我们预计SFB将不再增强肠道Tfh缺乏的K/BxN小鼠的脾Tfh反应。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，因为现代医学实践导致的生物失调可能会通过影响TFH细胞来触发自身免疫。这一建议将有助于我们了解自身免疫的发病机制，并为新的治疗方法提供新的基础。