Maroof Asher, Kaye Paul M
Immunology and Infection Unit, Hull York Medical School, and Department of Biology, University of York, Wentworth Way, York YO10 5YW, United Kingdom.
Infect Immun. 2008 Jan;76(1):239-49. doi: 10.1128/IAI.00643-07. Epub 2007 Nov 12.
Dendritic cells (DC) play an essential role in initiating and directing T-cell responses, in part by production of interleukin-12p70 (IL-12p70), IL-23, and IL-27. However, comparative studies on the capacity for cytokine production of DC subsets are rare. Here, we compare splenic CD8alpha+, CD4+, and double-negative (DN) DC, isolated 5 h to 28 days after Leishmania donovani infection, for (i) production of IL-12p70, (ii) accumulation of IL-12/23p40, IL-12p35, IL-23p19, and IL-27p28 mRNAs, and (iii) their capacity to direct CD4+ T-cell differentiation. At 5 h, conventional DC (cDC) accumulated mRNA for IL-12/23p40 (CD8alpha>CD4>DN), IL-23p19 (CD4>CD8alpha>DN), and IL-27p28 (CD8alpha>CD4>DN), in an infection dose-dependent manner. IL-12p70 was restricted to CD8alpha+ cDC, reflecting the subset-specific accumulation of IL-12p35 mRNA. In contrast, cDC from mice infected for 14 to 28 days accumulated little mRNA for IL-12p40 and IL-12p19, though IL-27p28 mRNA remained detectable (CD8alpha>DN>CD4). IL-12p70 secretion by CD8alpha+ cDC was also absent, reflecting deficient IL-12/23p40, rather than IL-12p35, mRNA accumulation. The capacity of CD8alpha+ cDC isolated early after infection to direct Th1 cell differentiation was mediated through IL-12/23p40, whereas this ability in CD4+ and DN cDC was independent of IL-12/23p40 and did not result from overexpression of Delta 4 Notch-like ligand. However, DN cDC produced gamma interferon (IFN-gamma) and also contained a rare population of CD11c(hi) DX5+ IFN-gamma-producing cells. Our data illustrate the extensive diversity in, and temporal regulation of, splenic cDC subsets during infection and suggest caution in interpreting data obtained with unfractionated or minimally purified DC.
树突状细胞（DC）在启动和引导T细胞反应中起着至关重要的作用，部分原因是其产生白细胞介素-12p70（IL-12p70）、IL-23和IL-27。然而，关于DC亚群产生细胞因子能力的比较研究很少。在这里，我们比较了在杜氏利什曼原虫感染后5小时至28天分离的脾脏CD8α+、CD4+和双阴性（DN）DC，以研究（i）IL-12p70的产生，（ii）IL-12/23p40、IL-12p35、IL-23p19和IL-27p28 mRNA的积累，以及（iii）它们引导CD4+ T细胞分化的能力。在5小时时，传统DC（cDC）以感染剂量依赖性方式积累IL-12/23p40（CD8α>CD4>DN）、IL-23p19（CD4>CD8α>DN）和IL-27p28（CD8α>CD4>DN）的mRNA。IL-12p70仅限于CD8α+ cDC，这反映了IL-12p35 mRNA的亚群特异性积累。相比之下，感染14至28天的小鼠的cDC积累的IL-12p40和IL-12p19 mRNA很少，尽管IL-27p28 mRNA仍可检测到（CD8α>DN>CD4）。CD8α+ cDC也不再分泌IL-12p70，这反映了IL-12/23p40而非IL-12p35 mRNA积累不足。感染后早期分离的CD8α+ cDC引导Th1细胞分化的能力是通过IL-12/23p40介导的，而CD4+和DN cDC的这种能力独立于IL-12/23p40，且不是由Delta 4 Notch样配体的过表达导致的。然而，DN cDC产生γ干扰素（IFN-γ）并且还包含一小群罕见的CD11c(hi) DX5+ IFN-γ产生细胞。我们的数据说明了感染期间脾脏cDC亚群的广泛多样性和时间调节，并建议在解释未分级或最低限度纯化的DC获得的数据时要谨慎。
