Tissue Regulatory T Cells in Mucosal Infection

粘膜感染中的组织调节 T 细胞

• 批准号: 10593457
• 负责人: Jennifer M Lund
• 金额: $ 54.22万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-11-07 至 2023-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10593457
• 关键词: Ablation; Adipose tissue; Antigens; Area; Attenuated; Autoimmunity; Biopsy; Blood; CD4 Positive T Lymphocytes; Cells; Characteristics; Data Set; Disease; Drug or chemical Tissue Distribution; Equilibrium; Excision; Flow Cytometry; Focal Infection; Frequencies; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genital; Genitalia; Graft Tolerance; Human; Human Herpesvirus 2; Immune; Immune response; Immunity; Immunofluorescence Immunologic; Immunologic Memory; Impairment; Individual; Infection; Inflammation; Inflammatory Response; Injury; Investigation; Kinetics; Location; Maintenance; Mediating; Memory; Methods; Modeling; Mucous Membrane; Mus; Pathology; Peripheral; Peripheral Blood Mononuclear Cell; Phase; Play; Property; Regulation; Regulatory T-Lymphocyte; Role; Sampling; Site; Skin; Sorting - Cell Movement; Space Perception; Specificity; Stains; T cell response; T memory cell; Therapeutic; Time; Tissues; Vaccine Design; Vagina; Viral; Virus Diseases; Virus Replication; Visceral; acute infection; anti-tumor immune response; antiviral immunity; arm; clinically significant; combat; draining lymph node; effector T cell; fetal; flexibility; genital herpes; human tissue; immunopathology; insight; lymphoid organ; mouse model; novel; novel vaccines; pathogen; penis foreskin; peripheral tolerance; prevent; rational design; response; tool; transcriptome; tumor; vaccine platform

PROJECT SUMMARY/ABSTRACT Regulatory T cells (Tregs) are a subset of CD4 T cells that are essential for the maintenance of peripheral tolerance, yet their precise roles during infections remain an active area of investigation. It is well-documented that following certain infections, Tregs are required to attenuate an overly robust immune response to prevent collateral damage to self-tissues. However, we have demonstrated that removal of Tregs prior to infection with Herpes Simplex Virus, type 2 (HSV-2), among other infections, results in delayed clearance of the pathogen, suggesting that the presence of Tregs can be critical to facilitating an appropriately robust and protective immune response. These differing results emphasize that the role played by Tregs during infections is context-dependent, and thus we propose here to focus on the location of the cells and the time post-infection as key factors that influence the role that Tregs play during mucosal virus infection. Recent evidence suggests that there exists a distinct subset of Tregs known as tissue Tregs. These cells have been best-characterized in skin and visceral adipose tissue, where they function to limit inflammation, though it has been suggested that tissue Tregs in other locations function to prevent autoimmunity, to promote fetal and graft tolerance, and to impair anti-tumor immune responses in various non-lymphoid tissues. However, despite the hypothesized role of tissue Tregs in controlling local inflammation to prevent autoimmunity and immunopathology, local immune responses are routinely and beneficially generated against mucosal infections, often without excessive tissue destruction at the infection site, and we thus hypothesize that tissue Tregs are involved in mediating this balance. Additionally, as effector T cell immune memories remain following infection clearance, we hypothesize that regulatory memory also persists such that these tissue memory T cell responses can be controlled under both homeostatic conditions as well as upon pathogen re-encounter to promote local tissue integrity. Therefore, we propose to extend our investigations of the role of Tregs during mucosal virus infection, now with a focus on the presence and consequences of tissue Tregs on anti-viral immune responses in mice and humans. Tissue-resident memory T cells have been intensely studied in recent years, and are now the basis for a promising new vaccine platform, so it is imperative that we understand how such tissue T cell responses might be regulated in order to support tissue protection in the face of a robust immune response.

项目总结/摘要 调节性T细胞（Treg）是CD 4 T细胞的一个亚群，其对于维持外周血淋巴细胞的增殖和分化至关重要。 然而，它们在感染过程中的确切作用仍然是一个活跃的研究领域。有充分的证据证明 在某些感染后，需要TGFs来减弱过度强烈的免疫反应，以防止 对自身组织的附带伤害然而，我们已经证明，在感染前去除THP， 单纯疱疹病毒2型（HSV-2），在其它感染中，导致病原体的延迟清除， 这表明，THBE的存在对于促进适当的强大和保护性免疫至关重要， 反应这些不同的结果强调了TdR在感染过程中所起的作用是依赖于环境的， 因此，我们在此建议将重点放在细胞的位置和感染后的时间作为关键因素， 影响了THBE在粘膜病毒感染过程中的作用。 最近的证据表明，存在一个独特的Tclasses子集，称为组织Tclasses。这些细胞具有 在皮肤和内脏脂肪组织中，它们的作用是限制炎症， 已经提出，在其它位置的组织T细胞具有防止自身免疫、促进胎儿和 移植物耐受性，以及损害各种非淋巴组织中的抗肿瘤免疫应答。但尽管 假设组织凝血酶在控制局部炎症以防止自身免疫中的作用， 在免疫病理学中，局部免疫应答常规地且有益地针对粘膜感染产生， 通常在感染部位没有过度的组织破坏，因此我们假设组织THP是 参与调解这种平衡。此外，由于效应T细胞免疫记忆在感染后仍然存在， 清除，我们假设调节记忆也持续存在，使得这些组织记忆T细胞 在体内平衡条件下以及在病原体再次相遇时， 促进局部组织完整性。因此，我们建议扩大我们的调查的作用， 粘膜病毒感染，现在的重点是存在和后果的组织THEORY抗病毒 小鼠和人类的免疫反应。近年来，组织驻留记忆T细胞已被广泛研究 多年来，现在是一个有前途的新疫苗平台的基础，所以我们必须了解如何 这样的组织T细胞反应可能受到调节，以便在面对强大的免疫缺陷时支持组织保护。 免疫反应