Tissue Regulatory T Cells in Mucosal Infection

粘膜感染中的组织调节 T 细胞

• 批准号: 10291399
• 负责人: Jennifer M Lund
• 金额: $ 11.19万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH 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 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10291399
• 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.

项目概要/摘要 调节性 T 细胞 (Treg) 是 CD4 T 细胞的一个子集，对于维持外周神经系统至关重要。 耐受性，但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。这是有据可查的 在某些感染后，Tregs 需要减弱过于强烈的免疫反应，以预防 对自身组织造成附带损害。然而，我们已经证明，在感染前去除Tregs 单纯疱疹病毒 2 型 (HSV-2) 以及其他感染会导致病原体清除延迟， 表明 Tregs 的存在对于促进适当稳健和保护性免疫至关重要 回复。这些不同的结果强调，Tregs 在感染过程中发挥的作用是依赖于环境的， 因此，我们在这里建议重点关注细胞的位置和感染后的时间作为关键因素 影响Tregs在粘膜病毒感染过程中发挥的作用。 最近的证据表明，存在一个独特的 Tregs 子集，称为组织 Tregs。这些细胞有 其在皮肤和内脏脂肪组织中的特征最为明显，它们的作用是限制炎症，尽管它 有人提出，其他部位的组织 Tregs 具有预防自身免疫、促进胎儿和胎儿发育的功能。 移植物耐受性，并损害各种非淋巴组织的抗肿瘤免疫反应。然而，尽管 组织 Tregs 在控制局部炎症以预防自身免疫和 免疫病理学，针对粘膜感染定期产生有益的局部免疫反应， 通常在感染部位没有过度的组织破坏，因此我们假设组织 Tregs 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 在稳态条件下以及病原体再次遇到病原体时都可以控制反应 促进局部组织完整性。因此，我们建议扩大对 Tregs 的作用的研究 粘膜病毒感染，现在重点关注组织 Tregs 的存在及其抗病毒作用的后果 小鼠和人类的免疫反应。近年来，组织驻留记忆 T 细胞得到了深入研究。 多年来，现在是有前途的新疫苗平台的基础，因此我们必须了解如何 此类组织 T 细胞反应可能会受到调节，以支持面对强大的组织保护。 免疫反应。