Tissue Regulatory T Cells in Mucosal Infection

粘膜感染中的组织调节 T 细胞

• 批准号: 10769945
• 负责人: Jennifer M Lund
• 金额: $ 3.05万
• 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 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10769945
• 关键词: Ablation; Adipose tissue; Antigens; Area; Attenuated; Autoimmunity; Biopsy; Blood; CD4 Positive T Lymphocytes; Cell physiology; 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; Space Perception; Specificity; Stains; T cell response; T memory cell; T-Cell Depletion; 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; memory acquisition; mouse model; novel; novel vaccines; pathogen; penis foreskin; peripheral tolerance; prevent; rational design; response; restraint; tissue resident memory T cell; 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.

项目摘要/摘要 调节性T细胞（Tregs）是CD4 T细胞的子集，对于维持外围至关重要 耐受性，但是它们在感染过程中的确切作用仍然是一个积极的调查领域。它有充分的记录 在某些感染之后，需要Treg衰减过度强大的免疫反应以防止 对自我组织的附带损害。但是，我们已经证明了在感染之前去除Treg 单纯疱疹病毒2型（HSV-2），除其他感染外，导致病原体的清除延迟， 暗示Treg的存在对于促进适当的强大和保护性免疫至关重要 回复。这些不同的结果强调，Tregs在感染过程中所扮演的作用与上下文有关， 因此，我们在这里提议关注细胞的位置以及感染后的时间作为关键因素 影响Tregs在粘膜病毒感染中扮演的作用。 最近的证据表明，存在一个被称为组织Treg的Treg的独特子集。这些细胞具有 在皮肤和内脏脂肪组织中最能表征最佳的特征，它们的作用以限制炎症，尽管 有人建议其他位置的组织Treg可以防止自身免疫性，以促进胎儿和 移植物的耐受性，以损害各种非淋巴组织中的抗肿瘤免疫反应。但是，尽管如此 组织Treg在控制局部炎症中的假设作用，以防止自身免疫和 免疫病理学，局部免疫反应通常是针对粘膜感染的，有益的， 通常在感染部位没有过多的组织破坏，因此我们假设组织Treg是 参与调解这种平衡。此外，随着效应t细胞免疫记忆在感染后仍保持 清除率，我们假设调节记忆也持续存在，使得这些组织记忆T细胞 可以在稳态条件以及病原体重新遇到的情况下控制反应 促进局部组织完整性。因此，我们建议扩展对Tregs在 粘膜病毒感染，现在侧重于组织对抗病毒的存在和后果 小鼠和人类的免疫反应。最近对组织居住的记忆T细胞进行了深入研究 多年，现在是一个有前途的新疫苗平台的基础，因此我们必须了解如何了解 这样的组织T细胞反应可能会受到调节，以便面对强大的组织保护 免疫反应。