Williams Charlotte A, Harry Rachel A, McLeod Julie D
Centre for Research in Biomedicine, Faculty of Applied Sciences, University of the West of England, Bristol BS16 1QY, United Kingdom.
Immunology. 2008 May;124(1):89-101. doi: 10.1111/j.1365-2567.2007.02743.x. Epub 2007 Dec 7.
Dendritic cells (DC) are sensitive to their local environment and are affected by proximal cell death. This study investigated the modulatory effect of cell death on DC function. Monocyte-derived DC exposed to apoptotic Jurkat or primary T cells failed to induce phenotypic maturation of the DC and were unable to support CD4+ allogeneic T-cell proliferation compared with DC exposed to lipopolysaccharide (LPS) or necrotic cells. Apoptotic cells coincubated with LPS- or necrotic cell-induced mature DC significantly suppressed CD80, CD86 and CD83 and attenuated LPS-induced CD4+ T-cell proliferation. Reduced levels of interleukin-12 (IL-12), IL-10, IL-6, tumour necrosis factor-alpha and interferon-gamma (IFN-gamma) were found to be concomitant with the suppressive activity of apoptotic cells upon DC. Furthermore, intracellular staining confirmed IFN-gamma expression by DC in association with apoptotic environments. The specific generation of IFN-gamma by DC within apoptotic environments is suggestive of an anti-inflammatory role by the induction of indoleamine 2,3-dioxygenase (IDO). Both neutralization of IFN-gamma and IDO blockade demonstrated a role for IFN-gamma and IDO in the suppression of CD4+ T cells. Moreover, we demonstrate that IDO expression within the DC was found to be IFN-gamma-dependent. Blocking transforming growth factor-beta (TGF-beta) also produced a partial release in T-cell proliferation. Our study strongly suggests that apoptosis-induced DC suppression is not an immunological null event and two prime mediators underpinning these functional effects are IFN-gamma-induced IDO and TGF-beta.
树突状细胞（DC）对其局部环境敏感，并受近端细胞死亡的影响。本研究调查了细胞死亡对DC功能的调节作用。与暴露于脂多糖（LPS）或坏死细胞的DC相比，暴露于凋亡性Jurkat细胞或原代T细胞的单核细胞衍生DC未能诱导DC的表型成熟，且无法支持CD4 + 异基因T细胞增殖。与LPS或坏死细胞诱导的成熟DC共孵育的凋亡细胞显著抑制CD80、CD86和CD83，并减弱LPS诱导的CD4 + T细胞增殖。发现白细胞介素-12（IL-12）、IL-10、IL-6、肿瘤坏死因子-α和干扰素-γ（IFN-γ）水平降低与凋亡细胞对DC的抑制活性相关。此外，细胞内染色证实DC在凋亡环境中表达IFN-γ。DC在凋亡环境中特异性产生IFN-γ提示通过诱导吲哚胺2,3-双加氧酶（IDO）发挥抗炎作用。IFN-γ中和和IDO阻断均证明IFN-γ和IDO在抑制CD4 + T细胞中起作用。此外，我们证明DC内IDO的表达是IFN-γ依赖性的。阻断转化生长因子-β（TGF-β）也部分解除了对T细胞增殖的抑制。我们的研究强烈表明，凋亡诱导的DC抑制并非免疫无效事件，支撑这些功能效应的两个主要介质是IFN-γ诱导的IDO和TGF-β。
