T cell regulation by IDO-competent plasmacytoid dendritic cells

IDO 活性浆细胞样树突状细胞对 T 细胞的调节

• 批准号: 7847624
• 负责人: Andrew Lee Mellor
• 金额: $ 36.75万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-22 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7847624
• 关键词: Allergic Disease; Allografting; Amino Acids; Antigens; Autoantigens; Autoimmune Diseases; Autoimmune Process; CTLA4-Ig; Cells; Cellular Stress; Cellular Stress Response; Chronic; Clinical; Dendritic Cells; Dioxygenases; Disease Progression; Enzymes; Exhibits; Goals; Graft Rejection; Growth; Human; Immune; Immune response; Immunity; Immunization; Immunocompetent; Immunosuppression; Immunosuppressive Agents; Immunotherapy; Individual; Infection; Inflammation; Inflammatory; Insulin-Dependent Diabetes Mellitus; Interferon Type I; Interferons; Islet Cell; Islets of Langerhans; Knowledge; Ligands; Ligation; Mediating; Metabolic; Methods; Molecular; Mus; Pathway interactions; Pharmaceutical Preparations; Phenotype; Population; Production; Reagent; Regulatory T-Lymphocyte; Rest; Signal Pathway; Signal Transduction; Site; Skin; Skin Transplantation; Skin graft; Spleen; Suppressor-Effector T-Lymphocytes; Syndrome; T cell regulation; T cell response; T-Lymphocyte; Testing; Tetradecanoylphorbol Acetate; Therapeutic; Time; Tissue Transplantation; Tissues; Transplantation; Tryptophan; Tumor Promoters; Work; adaptive immunity; biological adaptation to stress; cell type; cytokine; immunogenic; improved; indoleamine; innovation; insight; lymph nodes; melanoma; mouse model; neoplastic cell; pathogen; public health relevance; receptor; response; skin allograft; tumor; tumor progression

DESCRIPTION (provided by applicant): The paradigm that inflammation stimulates adaptive immunity is well established. Paradoxically, mounting evidence reveals that some forms of inflammation create local suppression, particularly in tissues subjected to chronic inflammation caused by persistent infections and developing tumors. Suppressive inflammation may facilitate tumor progression and promote pathogen persistence in immunocompetent individuals by inhibiting T cell responses to tumor and pathogen antigens encountered in these tissues and in associated draining lymph nodes. However, the underlying mechanisms that create and maintain local suppression in inflamed tissues are not well defined. Elucidating the mechanisms that promote local suppression in inflamed tissues will provide critical new insights and opportunities to improve therapeutic manipulations to treat hyper-immune syndromes such as transplant rejection, and autoimmune and allergic diseases by introducing donor (all) and self (auto) antigens at the same time as boosting immune suppressor activity. In previous work, we identified rare populations of plasmacytoid dendritic cells (pDCs) in humans and mice uniquely competent to express the immunosuppressive enzyme indoleamine 2,3 dioxygenase (IDO). In mice, interferon type I (IFN1) was the obligate upstream IDO inducer in splenic IDO-competent pDCs after B7 ligation. However, IFN1 production by pDCs was dependent on IDO activity, revealing that IDO amplified its own expression in IDO-competent pDCs via a cell autonomous IFN1-dependent pathway. Unlike their counterparts in spleen, pDCs in draining lymph nodes (dLNs) associated with melanoma growth expressed IDO constitutively, exhibited potent suppressor activity and activated regulatory CD4+CD25+ T cells (Tregs). We hypothesize that the ability of IDO-competent pDCs to create local suppression is critically dependent on cooperative interactions between pDCs and Tregs that amplify IDO expression, which triggers suppressor activity in both cell types. In preliminary studies we show that topical treatment of mice with the pro-inflammatory reagent and tumor promoter phorbol myristate acetate (PMA) paradoxically creates potent local suppression in skin dLNs by activating pDCs to express IDO, which in turn activate Tregs via IDO. The objective of studies proposed is to elucidate the mechanisms that induce dLN pDCs to express IDO (Aim 1), and activate Treg bystander suppressor activity via IDO (Aim 2) after PMA treatment. New knowledge generated will be used to guide and evaluate innovative methods to enhance local IDO expression during immunization, skin grafting and during autoimmune type I diabetes progression to block T cell mediated destruction of skin allografts and pancreatic islet cells, respectively. PUBLIC HEALTH RELEVANCE Studies proposed focus on a small subset of dendritic cells that completely suppress T cell responses to antigens in inflamed tissues when they receive particular signals from the tissue microenvironment. To create suppressive tissue microenvironments, dendritic cells must interact with a small subset of regulatory T cells via specific signaling pathways. Recently, we discovered that skin inflammation provoked by `painting' with a pro-inflammatory reagent commonly used in mouse models of tumor progression induces potent suppressor activity mediated by dendritic cells in skin draining lymph nodes. This observation provides a rationale for treating mice with donor allograft and self-antigens to induce tolerance that will protect skin grafts and pancreatic islet cells from T cell mediated destruction. 1

描述（由申请人提供）：炎症刺激适应性免疫的范例已充分确立。奇怪的是，越来越多的证据表明，某些形式的炎症会产生局部抑制，特别是在持续感染和肿瘤发展引起的慢性炎症组织中。抑制性炎症可能通过抑制T细胞对这些组织和相关引流淋巴结中遇到的肿瘤和病原体抗原的应答，促进肿瘤进展并促进病原体在免疫活性个体中的持续存在。然而，在炎症组织中产生和维持局部抑制的潜在机制尚未明确。阐明在发炎组织中促进局部抑制的机制将提供关键的新见解和机会，以通过引入供体（所有）和自身（自体）抗原同时增强免疫抑制剂活性来改善治疗操作以治疗超免疫综合征，如移植排斥，以及自身免疫和过敏性疾病。在以前的工作中，我们确定了人类和小鼠中罕见的浆细胞样树突状细胞（pDC）群体，其独特的能力是表达免疫抑制酶吲哚胺2，3双加氧酶（IDO）。在小鼠中，I型干扰素（IFN 1）是B7连接后脾IDO感受态pDC中的专性上游IDO诱导剂。然而，由pDC产生的IFN 1依赖于IDO活性，这揭示了IDO通过细胞自主IFN 1依赖性途径在IDO感受态pDC中扩增其自身的表达。与脾脏中的对应物不同，与黑色素瘤生长相关的引流淋巴结（dLN）中的pDC组成性表达IDO，表现出有效的抑制活性并活化调节性CD 4 + CD 25 + T细胞（T细胞）。我们假设IDO-感受态pDC产生局部抑制的能力关键依赖于pDC和TdR之间的协同相互作用，其放大IDO表达，这在两种细胞类型中触发抑制剂活性。在初步研究中，我们表明，用促炎剂和肿瘤促进剂佛波醇肉豆蔻酸酯乙酸酯（PMA）局部治疗小鼠，通过激活pDC表达IDO，这反过来又通过IDO激活TLN，矛盾地在皮肤dLN中产生有效的局部抑制。提出的研究的目的是阐明在PMA处理后诱导dLN pDC表达IDO（Aim 1）并通过IDO（Aim 2）激活Treg旁观者抑制活性的机制。产生的新知识将用于指导和评估创新方法，以增强免疫接种，皮肤移植和自身免疫性I型糖尿病进展期间的局部IDO表达，以分别阻断T细胞介导的皮肤同种异体移植物和胰岛细胞的破坏。公共卫生相关性研究建议关注一小部分树突状细胞，当它们从组织微环境接收特定信号时，它们完全抑制T细胞对炎症组织中抗原的反应。为了创造抑制性组织微环境，树突状细胞必须通过特定的信号通路与一小部分调节性T细胞相互作用。最近，我们发现，皮肤炎症引起的'绘画'与促炎试剂通常用于小鼠模型的肿瘤进展诱导有效的抑制活性介导的树突状细胞在皮肤引流淋巴结。这一观察结果为用供体同种异体移植物和自身抗原治疗小鼠以诱导耐受性提供了理论基础，所述耐受性将保护皮肤移植物和胰岛细胞免受T细胞介导的破坏。1

项目成果

Total and differential white blood cell counts, high-sensitivity C-reactive protein, and the metabolic syndrome in non-affective psychoses.

• DOI: 10.1016/j.bbi.2012.08.016
• 发表时间: 2013-07
• 期刊: Brain, behavior, and immunity
• 作者: Miller BJ;Mellor A;Buckley P
• 通讯作者: Buckley P

Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects.

精神分裂症细胞因子改变的荟萃分析：临床状况和抗精神病药作用。

• DOI: 10.1016/j.biopsych.2011.04.013
• 发表时间: 2011-10-01
• 期刊: BIOLOGICAL PSYCHIATRY
• 影响因子: 10.6
• 作者: Miller, Brian J.;Buckley, Peter;Seabolt, Wesley;Mellor, Andrew;Kirkpatrick, Brian
• 通讯作者: Kirkpatrick, Brian

Meta-analysis of lymphocytes in schizophrenia: clinical status and antipsychotic effects.

• DOI: 10.1016/j.biopsych.2012.09.007
• 发表时间: 2013-05-15
• 期刊: BIOLOGICAL PSYCHIATRY
• 影响因子: 10.6
• 作者: Miller, Brian J.;Gassama, Bintou;Sebastian, Dale;Buckley, Peter;Mellor, Andrew
• 通讯作者: Mellor, Andrew

Cytosolic DNA sensing via the stimulator of interferon genes adaptor: Yin and Yang of immune responses to DNA.

• DOI: 10.1002/eji.201344407
• 发表时间: 2014-10
• 期刊: EUROPEAN JOURNAL OF IMMUNOLOGY
• 影响因子: 5.4
• 作者: Lemos, Henrique;Huang, Lei;McGaha, Tracy L.;Mellor, Andrew L.
• 通讯作者: Mellor, Andrew L.