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（由申请人提供）：外周组织居住的树突状细胞（DC）是启动原代T细胞免疫反应的专业抗原（AG）呈递细胞（APC）。为了实现这一目标，他们是：i）进行和处理AGS； ii）从周围迁移到排水淋巴结；和iii）原始T细胞。除了其有效的T细胞刺激功能外，外围组织驻留DCS在稳态条件下维持外周耐受性方面起着关键作用。启动免疫力或耐受性的关键步骤是将幼稚的CD4 T细胞启动和偏置到T助手（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）（TR）（耐受性）中。 DC通过DC对幼稚的CD4 T细胞的激活和偏置是由以下确定的： DC表面和模式DC细胞因子上T细胞刺激分子的水平受刺激（危险信号）在外周组织激活过程中的特征很大。作为示例，Dinitro胆红素（DNCB）激活皮肤DC会引起普遍的Th1反应，而FITC激活DC激活会产生Th2偏置的响应，而皮肤UV-B辐射则偏爱耐受性。相反，在没有组织损伤的情况下，刺激的性质仍然不清楚。此外，在人类中尚未分析参与周围组织驻留DC启动T细胞反应的机制。为了解决这些问题，一个允许分析不同类型的皮肤迁移（SMI）DC的T细胞刺激功能的模型，以及免疫抑制剂（危险信号）或耐受性刺激可能对皮肤DC施加的影响是理想的。我们和其他人以前已经根据分子CD14的表达来鉴定，两种皮肤迁移（SMI）DCS：i）SMICD14-DC，它们表现出成熟的APC和强幼稚T细胞刺激能力的表型。 II）SMICD14+ DC，具有更不成熟的APC表型和幼稚T细胞的弱刺激剂。 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敏化器）或UV-B辐射（Tr-driver刺激）。