Department of Pathology, Case Western Reserve University/University Hospitals Case Medical Center, Cleveland, OH 44106, USA.
J Immunol. 2012 Apr 1;188(7):3116-26. doi: 10.4049/jimmunol.1101313. Epub 2012 Feb 27.
Microbial molecules or cytokines can stimulate dendritic cell (DC) maturation, which involves DC migration to lymph nodes and enhanced presentation of Ag to launch T cell responses. Microbial TLR agonists are the most studied inducers of DC maturation, but type I IFN (IFN-I) also promotes DC maturation. In response to TLR stimulation, DC maturation involves a burst of Ag processing with enhanced expression of peptide-class II MHC complexes and costimulator molecules. Subsequently, class II MHC (MHC-II) synthesis and expression in intracellular vacuolar compartments is inhibited, decreasing Ag processing function. This limits presentation to a cohort of Ags kinetically associated with the maturation stimulus and excludes presentation of Ags subsequently experienced by the DC. In contrast, our studies show that IFN-I enhances DC expression of MHC-II and costimulatory molecules without a concomitant inhibition of subsequent MHC-II synthesis and Ag processing. Expression of mRNA for MHC-II and the transcription factor CIITA is inhibited in DCs treated with TLR agonists but maintained in cells treated with IFN-I. After stimulation with IFN-I, MHC-II expression is increased on the plasma membrane but is also maintained in intracellular vacuolar compartments, consistent with sustained Ag processing function. These findings suggest that IFN-I drives a distinctive DC maturation program that enhances Ag presentation to T cells without a shutdown of Ag processing, allowing continued sampling of Ags for presentation.
微生物分子或细胞因子可以刺激树突状细胞（DC）成熟，这涉及 DC 向淋巴结的迁移和增强 Ag 的呈递以启动 T 细胞反应。微生物 TLR 激动剂是研究最多的 DC 成熟诱导剂，但 I 型干扰素（IFN-I）也促进 DC 成熟。在 TLR 刺激下，DC 成熟涉及 Ag 处理的爆发，伴有肽-II 类 MHC 复合物和共刺激分子的表达增强。随后，细胞内空泡区室中 II 类 MHC（MHC-II）的合成和表达受到抑制，降低了 Ag 处理功能。这限制了与成熟刺激动力学相关的一组 Ag 的呈递，并排除了随后被 DC 经历的 Ag 的呈递。相比之下，我们的研究表明，IFN-I 增强了 DC 对 MHC-II 和共刺激分子的表达，而不会伴随随后 MHC-II 合成和 Ag 处理的抑制。用 TLR 激动剂处理的 DC 中 MHC-II 和转录因子 CIITA 的 mRNA 表达受到抑制，但在用 IFN-I 处理的细胞中则保持不变。用 IFN-I 刺激后，MHC-II 表达增加到质膜上，但也保持在细胞内空泡区室中，这与持续的 Ag 处理功能一致。这些发现表明，IFN-I 驱动一种独特的 DC 成熟程序，增强了 T 细胞的 Ag 呈递，而不会关闭 Ag 处理，从而允许继续对 Ag 进行采样以进行呈递。
