Mechanisms of reduced T cell autoimmunity with immune experience

免疫经验降低T细胞自身免疫的机制

• 批准号: 10632556
• 负责人: VAIVA D VEZYS
• 金额: $ 40.87万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-14 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10632556
• 关键词: Acute; Address; Affect; Animal Model; Animals; Antigen Presentation; Antigens; Autoantigens; Autoimmune; Autoimmunity; Blood; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Communication; Cell Count; Cell division; Cells; Complex; Data; Developed Countries; Developing Countries; Development; Diabetes Mellitus; Disease; Elements; Endothelial Cells; Environment; Environmental Exposure; Environmental Impact; Epigenetic Process; Event; Exposure to; Factor X; Flow Cytometry; Fluorescence Microscopy; Future; Gene Expression Profile; Hygiene; Immune; Immune Tolerance; Immunity; Inbred NOD Mice; Incidence; Infection; Inflammatory Bowel Diseases; Inguinal lymph node group; Insulin-Dependent Diabetes Mellitus; Interferons; Interleukin-6; Intestines; Knowledge; Link; Lymphatic Endothelial Cells; Lymphocytic choriomeningitis virus; Lymphoid Tissue; Measures; Microbe; Mucous Membrane; Multiple Sclerosis; Mus; Outcome; Ovum; Parasites; Parasitic infection; Pathology; Patients; Penetrance; Peptide/MHC Complex; Phenotype; Play; Probability; Production; Recording of previous events; Reticular Cell; Speed; Stains; Stimulus; Stromal Cells; T cell response; T-Cell Activation; T-Lymphocyte; TNF gene; Testing; Therapeutic Intervention; Time; Tissues; Virus Diseases; Work; adaptive immune response; adaptive immunity; antigen-specific T cells; base; conditioning; experience; germ free condition; in vivo imaging; lymph nodes; microbial; mouse model; negative affect; novel; programs; public health relevance; transcription factor; transcriptome sequencing

The hygiene hypothesis states that there is an inverse correlation between exposure to microbes and the development of autoimmunity, i.e., the “cleaner” your environment is, the higher probability autoimmunity will develop. The reason for this is unclear. Thus, there are outstanding gaps in our knowledge about the hygiene hypothesis, including what changes occur in the host after microbial exposure and how this affects self-specific immunity leading to decreased autoimmunity. We have replicated aspects of the hygiene hypothesis using tractable, antigen-specific mouse models of infection and autoimmunity. Our data show that previous induction of T cell immunity under different conditioning contexts (infection or interaction with self-antigen) drives decreased self-specific CD8 T cell activation months later. The presence of anergic OTI T cells decreases future autoimmune pathology, as both the proliferation and function of self-specific CD8 T cells is blunted. We observe the same outcome in LCMV immune mice and in `dirty' mice. Previous immune experience is linked to earlier induction of a tolerant signature in responding self-specific CD8 T cells. This is specific for self-antigen, as foreign-antigen-specific T cell responses are unaffected. These aims will test the hypothesis that previous T cell responses alter self-antigen production and/or presentation in lymphoid tissue to speed tolerance induction. Aim 1 will determine whether changes in stromal cells in lymph nodes contribute to decreased self-specific CD8 T cell activation in immune-experienced mice. OTI cell division in iFABP-ova mice is reduced 60h post priming in inguinal LN of immune-experienced hosts, which is driven by non-migratory cells. As stromal cells in LN can produce tissue-restricted antigens, changes in these cells may negatively affect self-specific CD8 T cell activation. We will evaluate the number, epigenetic and phenotypic signature of LN stromal cells in naïve and immune-experienced mice and test if type I IFN, IFN, IL-6 or TNF, are important for the observed changes. Aim 2 will establish whether increased self-antigen presentation on LN stromal cells is responsible for decreased autoimmunity. We will evaluate expression of tissue-restricted antigens in immune-experienced animals, as well as factors important for their presentation, such as AIRE and DEAF1. Expression of these will be quantified in conjunction with staining for Kb-SIINFEKL complexes, as well as in vivo imaging of T cells in live mice. Overall, this application will determine the novel mechanisms by which self-antigen production or presentation is altered due to previous environmental programming from the adaptive immune response. It also addresses the important, but mechanistically unresolved, hygiene hypothesis, a fundamental topic intersecting TCR responsiveness with environmental impact, leading to vastly different outcomes of tolerance or autoimmunity.

卫生假说指出，暴露于微生物和微生物之间存在负相关性。 自身免疫的发展，即，你的环境越“干净”， 开发.原因尚不清楚。因此，在我们对卫生的认识方面存在着突出的差距。 假设，包括微生物暴露后宿主发生了什么变化，以及这如何影响自身特异性 导致自身免疫力下降。我们复制了卫生假说的各个方面， 易于处理的抗原特异性感染和自身免疫小鼠模型。我们的数据显示， T细胞免疫在不同条件下（感染或与自身抗原相互作用）的驱动 几个月后，自身特异性CD 8 T细胞活化减少。无反应性OTI T细胞的存在减少了未来的 这可能导致自身免疫性病理学，因为自身特异性CD 8 T细胞的增殖和功能都被钝化。我们观察 LCMV免疫小鼠和“脏”小鼠的结果相同。以前的免疫经验与早期 在应答的自身特异性CD 8 T细胞中诱导耐受性特征。这对自身抗原是特异性的，因为 外源抗原特异性T细胞应答不受影响。这些目标将测试假设，以前的T 细胞应答改变自身抗原的产生和/或在淋巴组织中的呈递以加速耐受性诱导。 目的1将确定淋巴结中基质细胞的变化是否有助于降低自身特异性CD 8 免疫小鼠中的T细胞活化。iFABP-ova小鼠中的OTI细胞分裂在引发后60小时减少 在免疫经历的宿主的腹股沟LN中，其由非迁移细胞驱动。由于LN中的基质细胞可以 产生组织限制性抗原，这些细胞的变化可能会对自身特异性CD 8 T细胞产生负面影响。 activation.我们将评估LN基质细胞的数量、表观遗传和表型特征， 免疫经验的小鼠，并测试I型IFN、IFN β、IL-6或TNF β是否对观察到的变化重要。 目的2将确定LN基质细胞上自身抗原提呈的增加是否是LN基质细胞上自身抗原提呈减少的原因。 自身免疫我们也将评估组织限制性抗原在免疫动物中的表达 作为重要的因素，他们的介绍，如AIRE和DEAF 1。这些表达将在 结合Kb-SIINFEKL复合物的染色，以及活小鼠中T细胞的体内成像。总的来说， 本申请将确定改变自身抗原产生或呈递的新机制 这是由于适应性免疫反应的先前环境编程。它还涉及 一个重要的，但机制上尚未解决的卫生假说，一个基本的主题交叉TCR 反应性与环境影响，导致耐受性或自身免疫性的截然不同的结果。