Immune role of CD14+ & CD14- human skin dendritic cells

CD14的免疫作用

• 批准号: 6712216
• 负责人: Adriana T Larregina
• 金额: $ 22.29万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6712216
• 关键词: AP1 protein; CD14 molecule; T lymphocyte; antigen presentation; cell adhesion; cell cell interaction; cytokine; dendritic cells; human tissue; immune response; immunomodulators; nuclear factor kappa beta; skin; tissue /cell culture

DESCRIPTION (provided by applicant): Peripheral tissue-resident dendritic cells (DCs) are professional antigen (Ag) presenting cells (APCs) that initiate primary T cell immune responses. To achieve this, they: i) take up and process Ags; ii) migrate from periphery to draining lymph nodes; and iii) prime naive T cells. Besides their potent T cell stimulatory function, peripheral tissue resident-DCs play a key role in maintenance of peripheral tolerance in steady-state conditions. A crucial step for initiation of immunity or tolerance is the priming and biasing of naive CD4 T cells into T helper (Th) 1 cells (cellular immune response), Th2 cells (humoral immunity) or regulatory T cells (TR) (tolerance). Activation and biasing of naive CD4 T cells by DCs are determined mainly by: i) the characteristics of the DC-T cell synapse, and ii) the pattern of cytokines secreted by DCs during DC-T cell contact. The level of T cell stimulatory molecules on the DC surface and the pattern DC cytokines are influenced greatly by the characteristics of the stimuli (danger signals) during activation of DCs in peripheral tissues. As examples, activation of skin DCs by dinitrocholorobenzene (DNCB) induces a prevalent Th1 response, DC-activation by FITC generates a Th2-biased response and skin UV-B irradiation favors tolerance. Conversely, it is still not clear the nature of the stimuli that trigger steady migration of DCs from periphery in the absence of tissue damage. Moreover, the mechanisms involved in the initiation of T cell responses by peripheral tissue resident DCs have not been analyzed in humans. To address these questions a model of ex-vivo human skin explants that permits to analyze the T cell stimulatory function of different types of skin migratory (smi) DCs and the effect that immunostimulatorv (danger signals) or tolerogenic stimuli may exert on cutaneous DCs would be ideal. We and others have previously identified, based on the expression of the molecule CD14, two populations of skin migratory (smi)DCs: i) smiCD14- DCs, that exhibit phenotype of mature APCs and strong naive T cell stimulatory ability; and ii)smiCD14+ DCs, with a more immature APC phenotype and weak stimulators of naive T cells. In the present We propose to: 1) Compare the immune functions of smiCD14+DCs and smiCD14-DCs spontaneously mobilized from human skin explants, and 2) Determine activation and function of smiCD14+DCs and smiCD14-DCs from epidermal/dermal explants exposed to DNCB (a Th1-biasing sensitizer), FITC (a Th2-biasing sensitizer) or UV-B irradiation (TR-driving stimulus).

描述(申请人提供)：外周组织树突状细胞(DC)是专业的抗原(Ag)提呈细胞(APC)，启动初级T细胞免疫反应。为了做到这一点，他们：i)处理和处理AGS；ii)从周围迁移到引流的淋巴结处；iii)原始T细胞。除了其强大的T细胞刺激功能，外周组织驻留的DC在稳态条件下维持外周耐受中发挥着关键作用。启动免疫或耐受的关键步骤是将初始的CD4T细胞启动并偏向辅助性T细胞(Th)1细胞(细胞免疫反应)、Th2细胞(体液免疫)或调节性T细胞(Tr)(耐受性)。DC对初始CD4T细胞的激活和偏置主要取决于：1)DC-T细胞突触的特性；2)DC与T细胞接触时分泌的细胞因子模式。外周组织DC激活过程中刺激(危险信号)的特性对DC表面T细胞刺激分子的水平和DC细胞因子的形态有很大影响。例如，二硝基氯苯(DNCB)激活皮肤树突状细胞(DC)会诱导普遍的Th1反应，FITC激活DC会产生偏向Th2的反应，皮肤UV-B辐射有利于耐受。相反，在没有组织损伤的情况下，触发DC从外周稳定迁移的刺激的性质仍然不清楚。此外，人类外周组织树突状细胞启动T细胞反应的机制尚未被分析。为了解决这些问题，理想的方法是建立一个人体皮肤移植模型，该模型能够分析不同类型的皮肤移行树突状细胞的T细胞刺激功能，以及免疫刺激(危险信号)或耐受刺激对皮肤树突状细胞可能产生的影响。我们和其他人已经根据CD14分子的表达确定了两类皮肤迁移性(SMI)DC：i)smiCD14-DC，表现出成熟的APC表型和强大的幼稚T细胞刺激能力；以及ii)smiCD14+DC，具有较不成熟的APC表型和弱的幼稚T细胞刺激能力。在本研究中，我们建议：1)比较人皮肤外植体自发动员的smiCD14+DC和smiCD14-DC的免疫功能；2)测定经DNCB(Th1偏向增敏剂)、FITC(Th2偏向增敏剂)或UV-B照射(TR驱动刺激)的表皮/真皮外植体中smiCD14+DC和smiCD14-DC的激活和功能。