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

CD14的免疫作用

• 批准号: 6877157
• 负责人: Adriana T Larregina
• 金额: $ 22.28万
• 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 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6877157
• 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（由申请人提供）：外周组织驻留树突状细胞（DC）是专职抗原（Ag）呈递细胞（APC），可启动原发性T细胞免疫应答。为了实现这一点，它们：i）摄取和加工Ag; ii）从外周迁移到引流淋巴结;和iii）引发初始T细胞。外周组织驻留型DC除了具有强大的T细胞刺激功能外，还在维持稳态条件下的外周耐受中发挥关键作用。启动免疫或耐受性的关键步骤是初始CD 4 T细胞向T辅助（Th）1细胞（细胞免疫应答）、Th 2细胞（体液免疫）或调节性T细胞（TR）（耐受性）的引发和偏置。DC对初始CD 4 T细胞的活化和偏向主要由以下决定：i）DC-T细胞突触的特征，和ii）在DC-T细胞接触期间由DC分泌的细胞因子的模式。DC表面T细胞刺激分子的水平和DC细胞因子的模式受到外周组织中DC激活过程中刺激物（危险信号）的特性的极大影响。例如，通过二硝基氯苯（DNCB）激活皮肤DC诱导普遍的Th 1应答，通过FITC激活DC产生Th 2偏向的应答，并且皮肤UV-B照射有利于耐受。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，尚未在人体中分析外周组织驻留DC引发T细胞应答的机制。为了解决这些问题，离体人皮肤外植体的模型将是理想的，该模型允许分析不同类型的皮肤迁移（smi）DC的T细胞刺激功能以及免疫刺激物（危险信号）或致耐受性刺激物可能对皮肤DC施加的作用。我们和其他人先前已经基于分子CD 14的表达鉴定了两种皮肤迁移（smi）DC群体：i）smiCD 14-DC，其表现出成熟APC的表型和强的幼稚T细胞刺激能力;和ii）smiCD 14 + DC，其具有更不成熟的APC表型和弱的幼稚T细胞刺激物。本研究拟：1）比较从人皮肤组织块自发动员的smiCD 14 + DC和smiCD 14-DC的免疫功能; 2）测定DNCB（一种Th 1-偏置敏化剂）、FITC（一种Th 2-偏置敏化剂）或UV-B辐射（TR-驱动刺激）对表皮/真皮组织块的smiCD 14 + DC和smiCD 14-DC的激活和功能。