Regulation and function of nonlymphoid organ CD103 dendritic cells

非淋巴器官CD103树突状细胞的调节和功能

• 批准号: 8832406
• 负责人: Stephanie S Watowich
• 金额: $ 20万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8832406
• 关键词: Address; Animals; Antigen Presentation; Antigens; CD8B1 gene; Cell Maturation; Cell physiology; Cells; Cross Presentation; Cues; Data; Dendritic Cells; Dependence; Detection; Development; Down-Regulation; Engineering; Event; Exhibits; Gene Expression; Gene Targeting; Generations; Genetic Engineering; Genetic study; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Host Defense; Human; Immune; Immune System Diseases; Immune response; Immunologic Deficiency Syndromes; Immunotherapy; Inflammation; Interleukin-6; Invaded; Investigation; Knowledge; Learning; Liver; Location; Lung; Lymphocyte Activation; Lymphoid; Malignant Neoplasms; Mediating; Microbe; Molecular; Mus; Organ; Participant; Pathway interactions; Population; RNA Polymerase II; Regulation; Role; STAT protein; STAT3 gene; Signal Pathway; Signal Transduction; Skin; Stat5 protein; System; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic Uses; Tissues; Tumor Immunity; Viral; Wit; adaptive immunity; base; cancer cell; cancer therapy; cell mediated immune response; cell type; chromatin modification; cytokine; cytotoxic; design; human tissue; in vivo; lymph nodes; melanoma; mouse model; mycobacterial; neoplastic cell; particle; pathogen; peripheral tolerance; promoter; public health relevance; residence; response; tumor; tumor microenvironment

DESCRIPTION (provided by applicant): CD103+ dendritic cells (CD103+ DCs) are a critical immune subset that resides in nonlymphoid organs in the mouse such as skin, liver and lung. This DC population migrates to lymph nodes to induce adaptive immune responses and is notably proficient in cross-presentation of exogenous antigen to cytotoxic CD8+ T cells. Because of their tissue residence and function, CD103+ DCs are perfectly situated to regulate immune responses to tumors. However, little is understood about their role in cancer. CD103+ DCs are homologous to human tissue CD141+ DCs and DCs generated in GM-CSF for cancer therapy, and provide a genetically tractable system to understand these important DC populations. Recently, our lab and others found CD103+ DCs have a unique developmental pathway dependent on the cytokine GM-CSF, the signal transducer and activator of transcription STAT5 and the transcriptional regulator Id2. This signaling pathway correlates with enhanced DC-mediated tumor immunity. By contrast, we found that the tumor-associated cytokine IL-6 represses Id2 expression in DCs via STAT3 signaling, rendering reduced DC-mediated tumor immunity. The cellular and molecular mechanisms by which STAT5 and STAT3 control CD103+ DC functional responses remain unclear. These gaps in knowledge are important to address to provide better use of DCs in immunotherapy. Based on our data, we hypothesize that GM-CSF-STAT5 and IL-6-STAT3 signaling have opposite roles in regulating DC anti-tumor activity via their control of Id2 expression in DCs. We will test this hypothesis wit 3 project aims. In Aim 1, we will delineate mechanisms by which tissue- resident DCs stimulate anti-tumor immunity by investigating the roles for STAT5 and its target gene Id2 in CD103+ DCs. We will study whether and how STAT5 and Id2 control CD103+ DC maturation, antigen presentation, T lymphocyte stimulation, pre-DC accrual in nonlymphoid tissue, and DC-mediated anti-tumor activity. In Aim 2, we will elucidate DC-intrinsic signaling mechanisms that regulate DC function in melanoma tumors. We will investigate roles for STAT3 in DCs in Id2 downregulation, immune responses to melanoma and melanoma combination immunotherapy. In Aim 3, we will examine mechanisms by which STAT5 and STAT3 regulate Id2 expression in DC development. We will evaluate whether and how STAT5 and STAT3 control chromatin modifications, co-factor recruitment and RNA polymerase II association at the Id2 promoter in vivo. We anticipate this project to reveal cellular and molecular mechanisms by which CD103+ DC anti-tumor activity is regulated, paving the way for rational investigation into pathways controlling related human DC populations. This information could ultimately provide new opportunities to manipulate DCs in cellular therapy, cancer and/or immune disease.

描述（由申请人提供）：CD103+树突状细胞（CD103+ dc）是一个关键的免疫亚群，存在于小鼠的非淋巴器官中，如皮肤、肝脏和肺。这种DC种群迁移到淋巴结诱导适应性免疫反应，并特别精通外源抗原对细胞毒性CD8+ T细胞的交叉呈递。由于它们的组织驻留和功能，CD103+ dc完全处于调节肿瘤免疫反应的位置。然而，人们对它们在癌症中的作用知之甚少。CD103+ DC与人类组织CD141+ DC和在GM-CSF中产生的用于癌症治疗的DC同源，并提供了一个遗传可处理的系统来了解这些重要的DC群体。最近，我们的实验室和其他人发现CD103+ dc具有独特的发育途径，依赖于细胞因子GM-CSF，转录STAT5的信号转导和激活因子以及转录调节因子Id2。该信号通路与dc介导的肿瘤免疫增强相关。相比之下，我们发现肿瘤相关细胞因子IL-6通过STAT3信号抑制dc中Id2的表达，导致dc介导的肿瘤免疫降低。STAT5和STAT3控制CD103+ DC功能反应的细胞和分子机制尚不清楚。这些知识上的差距对于解决在免疫治疗中更好地利用dc至关重要。根据我们的数据，我们假设GM-CSF-STAT5和IL-6-STAT3信号通过控制DC中Id2的表达，在调节DC抗肿瘤活性方面具有相反的作用。我们将用3个项目目标来检验这一假设。在Aim 1中，我们将通过研究STAT5及其靶基因Id2在CD103+ dc中的作用来描述组织驻留dc刺激抗肿瘤免疫的机制。我们将研究STAT5和Id2是否以及如何控制CD103+ DC成熟、抗原呈递、T淋巴细胞刺激、非淋巴组织中DC前期积累以及DC介导的抗肿瘤活性。在Aim 2中，我们将阐明在黑色素瘤中调节DC功能的DC-内在信号机制。我们将研究STAT3在dc中Id2下调、黑色素瘤免疫应答和黑色素瘤联合免疫治疗中的作用。在Aim 3中，我们将研究STAT5和STAT3在DC发育过程中调节Id2表达的机制。我们将评估STAT5和STAT3是否以及如何在体内控制Id2启动子的染色质修饰、辅助因子募集和RNA聚合酶II结合。我们期望该项目揭示CD103+ DC抗肿瘤活性调控的细胞和分子机制，为合理研究控制相关人类DC群体的途径铺平道路。这一信息可能最终为在细胞治疗、癌症和/或免疫疾病中操纵dc提供新的机会。