Influence of Chemokine Receptors on T Cell Cytokine Profiles in Skin

趋化因子受体对皮肤 T 细胞细胞因子谱的影响

• 批准号: 8225940
• 负责人: James J. Campbell
• 金额: $ 20.55万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8225940
• 关键词: Adjuvant; Affect; Agonist; Antigens; Biological Assay; Blood; CC chemokine receptor 4; CCR6 gene; CD4 Positive T Lymphocytes; Carbohydrates; Cells; Characteristics; Cholera Toxin; Commit; Cutaneous; E-Selectin; Environment; GPR2 gene; Homing; IL17 gene; Immune; Immune response; Immunization; Immunology; Inflammation; Inflammatory; Interleukin-17; Ligands; Lymphoid; Mediating; Memory; Modeling; Mus; Organ; Patients; Play; Population; Process; Production; Psoriasis; Reaction; Research; Role; Signal Transduction; Skin; T cell response; T-Lymphocyte; Testing; Tissues; Topical application; Transgenic Organisms; Work; base; cell mediated immune response; chemokine receptor; cytokine; experience; immune function; imprint; in vivo; interest; lymph nodes; migration; novel; prevent; receptor; response; single molecule; trafficking; transcription factor

DESCRIPTION (provided by applicant): The subset of antigen-experienced CD4 T cells dedicated to skin immunology express the carbohydrate ligand for E-selectin (E-lig) along with chemokine receptor CCR4. We have developed an in vivo assay in which naive TCR-transgenic OT-II cells develop into skin-homing T cells in response to topically applied antigen. We have successfully used this assay to investigate the conditions required for naive cells to differentiate in to cutaneous memory cells, and to explore the role of CCR4 in the process by which T cells enter cutaneous tissue from the blood. Although CCR4-deficient OT-II cells are severely impaired in their ability to enter inflamed skin, they appear to replicate normally within the skin-draining lymph nodes (LN) in response to antigen. This assay employs an antigen/adjuvant combination that creates a psoriasis-like cytokine environment, generating populations of antigen-specific T cells that express IFN3 or IL17, but not common TH2-associated cytokines. CCR4-deficient T cells in this same assay did not produce IL-17, which we found to be the dominant cytokine produced by normal skin-imprinted E-lighi cells. Conversely, IFN3 expression was significantly increased for CCR4-deficient cells. To our knowledge, this is the first case in which the functional absence of a chemokine receptor has been observed to alter the TH cytokine profile of T cells responding to a given antigen. In this project, we propose to more fully explore this novel discovery, and test several hypotheses regarding the mechanism by which CCR4 ultimately influences the cytokine profile. We propose to assess expression of a wider variety of cytokines than those examined in our preliminary work to probe the full extent to which CCR4 influences this process. We will also look for differences in the expression of transcription factors associated with the various TH lineages. We will attempt to distinguish whether CCR4 influences the cytokine profile by guiding cells to a microenvironment within skin that is permissive for IL17 induction, or whether CCR4 signals directly influence TH imprinting. Furthermore, we will use various TLR ligands as adjuvants to alter the cytokine responses produced in our model, and assess the influence of CCR4 under these altered conditions. Finally, we will assess the ability of two other skin-associated chemokine receptors, CCR6 and CCR10, for their own potential to influence TH cytokine profiles in this assay. PUBLIC HEALTH RELEVANCE: We have made the unexpected discovery that a class of molecules called chemokine receptors can alter the cytokine response against a given antigen. Chemokine receptors are mainly known for their role in directing the migration of immune cells around the body as they engage in surveillance for unwanted invaders. We believe that our new discovery will open up an entirely new direction of research on how to positively manipulate the type of immune response in which a patient engages.

描述（由申请人提供）：专用于皮肤免疫学的抗原经验的CD4 T细胞的子集表达E-选择蛋白（E-LIG）的碳水化合物配体以及趋化因子受体CCR4。我们已经开发了一种体内测定，其中天真的TCR转基因OT-II细胞响应局部施用的抗原而形成皮肤染色的T细胞。我们已经成功地使用了该测定法来研究幼稚细胞与皮肤记忆细胞区分开所需的条件，并探索CCR4在T细胞从血液中进入皮肤组织的过程中的作用。尽管缺乏CCR4的OT-II细胞进入发炎的皮肤的能力严重受损，但它们似乎在响应抗原的响应于皮肤干燥的淋巴结（LN）中正常复制。该测定法采用抗原/辅助组合，产生牛皮癣样细胞因子环境，产生表达IFN3或IL17但不常见Th2相关的细胞因子的抗原特异性T细胞种群。该测定中的CCR4缺陷型T细胞没有产生IL-17，我们发现这是正常皮肤敏感的E-Lighi细胞产生的主要细胞因子。相反，对于CCR4缺陷型细胞，IFN3表达显着增加。据我们所知，这是观察到功能性缺乏趋化因子受体的第一种情况，可以改变对给定抗原反应的T细胞的TH细胞因子谱。在这个项目中，我们建议更全面地探索这一新颖的发现，并检验有关CCR4最终影响细胞因子概况的机制的几种假设。我们建议评估比初步工作中所检查的细胞因子的表达，以探测CCR4影响这一过程的全部程度。我们还将寻找与各种谱系相关的转录因子表达的差异。我们将尝试通过将细胞引导到皮肤中的微环境来区分CCR4是否会影响细胞因子的谱，该微环境允许IL17诱导，或者CCR4信号是否直接影响TH印迹。此外，我们将使用各种TLR配体作为佐剂来改变模型中产生的细胞因子反应，并评估CCR4在这些改变条件下的影响。最后，我们将评估另外两个与皮肤相关的趋化因子受体CCR6和CCR10的能力，以便在该测定中影响细胞因子谱的潜力。 公共卫生相关性：我们已经意外发现，一类称为趋化因子受体的分子可以改变针对给定抗原的细胞因子反应。趋化因子受体主要以指导体内免疫细胞迁移的作用，因为它们在进行不需要的入侵者的监视时。我们认为，我们的新发现将为如何积极操纵患者参与的免疫反应类型开辟一个全新的研究方向。