Molecular basis for the potency of IL-10-deficient dendritic cells as a highly efficient APC system for activating Th1 response
Molecular basis for the potency of IL-10-deficient dendritic cells as a highly efficient APC system for activating Th1 response
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DOI：
10.4049/jimmunol.174.8.4860
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发表时间：
2005-04-15
影响因子：
4.4
通讯作者：
Igietseme, JU
中科院分区：
文献类型：
--
作者：
He, Q;Moore, TT;Igietseme, JU
鉴定和靶向调节Th 1细胞诱导的新型免疫生物学因子对于设计针对某些细胞内病原体（包括衣原体）的有效疫苗至关重要。IL-10缺陷型树突状细胞（DC）是有效的APC和有效的细胞疫苗，其激活高频率的特异性Th 1细胞。为了阐明IL-10缺陷型APC系统效力的分子基础，我们测试了以下假设：衣原体Ag引发的IL-10敲除（IL-10 KO）DC在与T细胞活化相关的代谢特征方面定量和定性不同。采用RT-PCR、双向凝胶电泳和基于MALDI-TOF的蛋白质组学分析相结合的方法，对来自野生型和IL-10 KO小鼠的衣原体脉冲DC的转录和翻译活性进行了评估。IL-10缺乏引起脉冲DC的早期成熟和活化（即，高的CD 11 c、CD 40、CD 80、CD 83、CD 86、IL-1、IL-12和T细胞吸引趋化因子CCL 27/CTACK），并因此增强了加工和呈递Ag的能力，以实现快速和稳健的T细胞活化。支持比较蛋白质组学进一步揭示了IL-10缺陷型DC具有特异性免疫生物学特性，例如，吸引T细胞的趋化因子CCL 27/CTACK、钙依赖性蛋白激酶和IL-1/IL-12诱导剂NKR-P1 A（CD 161），其在免疫学上将它们与表达与抗炎、分化和代谢过程相关的分子的野生型DC区分开，抗IL-12分子过氧化物酶体增殖物激活受体-α和胸苷激酶。总的来说，这些结果提供了IL-10 KO APC的高Th 1活化能力的分子基础，并可能提供独特的免疫调节靶点时，设计针对由T细胞免疫控制的病原体的疫苗。
Identification and targeting of novel immunobiological factors that regulate the induction of Th1 cells are crucial for designing effective vaccines against certain intracellular pathogens, including Chlamydia. IL-10-deficient dendritic cells (DC) are potent APCs and effective cellular vaccines that activate a high frequency of specific Th1 cells. To elucidate the molecular basis for the potency of the IL-10-deficient APC system, we tested the hypothesis that Chlamydia Ag-primed IL-10 knockout (IL-10KO) DC are quantitatively and qualitatively distinct in their metabolic characteristics relating to T cell activation. Using a combination of RT-PCR, two-dimensional gel electrophoresis, and MALDI-TOF-based proteomics analyses, the transcriptional and translational activities of Chlamydia-pulsed DC from wild-type and IL-10KO mice were assessed. IL-10 deficiency caused early maturation and activation of pulsed DC (i.e., high CD11c, CD40, CD80, CD83, CD86, IL-1, IL-12, and the T cell-attracting chemokine CCL27/CTACK) and consequently an enhanced ability to process and present Ags for a rapid and robust T cell activation. Supporting comparative proteomics revealed further that IL-10 deficient DC possess specific immunobiological properties, e.g., the T cell-attracting chemokine CCL27/CTACK, calcium-dependent protein kinase, and the IL-1/IL-12 inducer, NKR-P1A (CD161), which differentiated them immunologically from wild-type DC that express molecules relating to anti-inflammatory, differentiative, and metabolic processes, e.g., the anti-IL-12 molecule peroxisome proliferator-activated receptor-alpha and thymidine kinase. Collectively, these results provide a molecular basis for the high Th1-activating capacity of IL-10KO APC and may provide unique immunomodulation targets when designing vaccines against pathogens controlled by T cell immunity.