Interleukin‐12 Production by Dendritic Cells
Interleukin‐12 Production by Dendritic Cells
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树突状细胞产生白介素-12
DOI：
--
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发表时间：
1996
期刊：
影响因子：
--
通讯作者：
W. Strober
中科院分区：
文献类型：
--
作者：
B. Kelsall;E. Stüber;M. Neurath;W. Strober
最近的研究表明，用抗gp39抗体治疗小鼠，在小鼠II型胶原诱导的关节炎模型中，在急性半同种异体移植物抗宿主病中，以及在同种异体特异性CTL反应中，即被认为是由Th1型T细胞介导的反应中，T细胞功能受到损害。另一方面，给予抗gp39抗体并不影响Th2 T细胞的反应，这表明CD40-CD40L相互作用对Th1细胞的发育比Th2 T细胞的发育更为关键。最近的研究还表明，树突状细胞(DC)能够驱动由IL-12介导的Th1 T细胞反应。此外，CD40对人单核细胞的刺激可导致IL-12的产生，提示表达CD40L的活化T细胞可能直接诱导抗原提呈细胞产生IL-12，从而在没有细胞内病原体的情况下产生Th1 T细胞反应。我们在一个允许精确控制细胞因子浓度的体外系统中，研究了CD40-CD40L相互作用是否在DC产生IL-12过程中起重要作用。最初我们发现，通过表达CD40L的成纤维细胞，FACS纯化的小鼠脾树突状细胞在CD40交联物作用下产生高水平的IL-12p40。然后，我们证明了DC在更生理的系统中也产生IL-12p40，使用卵白蛋白(OVA)冲击的纯化DC，然后与来自卵白蛋白T细胞受体转基因小鼠的LECAM-1hi T细胞培养。IL-10具有阻断CD40诱导的IL-12p40分泌的作用，IL-4部分抑制CD40诱导的IL-12p40分泌，增强IL-10介导的抑制作用。我们还在Th1介导的疾病--半抗原试剂(TNBS)诱导的结肠炎的实验模型中研究了这种相互作用的体内相关性。在Th1反应的诱导阶段给予抗gp39(CD40L)抗体完全阻止肠道固有层的CD4T细胞产生干扰素-γ，也阻止了疾病的临床和组织学证据。在进一步的研究中，我们表明，预防疾病活动是由于抑制了IL-12的分泌。因此，将重组IL12p75异源二聚体注射到TNBS+抗gp39治疗的小鼠体内，逆转了抗gp39的作用，并导致了严重的疾病活动。综上所述，这些发现提示DC产生IL-12是响应CD40信号，IL-4诱导Th2形成的一个机制是通过与IL-10共同作用抑制DC产生IL-12，CD40L-CD40相互作用对体内依赖IL-12的Th1 T细胞的启动至关重要。
Recent studies have demonstrated that the treatment of mice with anti-gp39 antibodies impairs T-cell functions in the murine collagen type II-induced arthritis model, in acute semi-allogenic graft-versus-host disease, and in the allo-specific CTL-reaction, that is, reactions that are believed to be mediated by Th1-type T cells. On the other hand, the administration of anti-gp39 antibody did not influence Th2 T-cells responses, suggesting that CD40-CD40L interactions are more crucial for Th1 than Th2 T-cell development. Recent studies also demonstrate that dendritic cells (DC) are capable of driving a Th1 T-cell response that is mediated by IL-12. In addition, stimulation of CD40 on human monocytes results in IL-12 production, suggesting that activated T cells expressing CD40L may directly induce the production of IL-12 by antigen-presenting cells, thus allowing for the generation of a Th1 T-cell response in the absence of intracellular pathogens. We investigated whether the CD40-CD40L interaction was important in the production of IL-12 by DCs in an in vitro system that allowed precise control of cytokine concentrations. Initially we showed that FACS-purified mouse spleen DCs produce high amounts of IL-12 p40 in response to CD40 crosslinking by CD40L-expressing fibroblasts. We then demonstrate that DCs also produce IL-12 p40 in a more physiologic system using purified DCs pulsed with ovalbumin (OVA) and then cultured with LECAM-1hi T cells from ovalbumin T-cell receptor transgenic mice. Finally, we show that IL-10 has a potent capacity to shut down CD40-induced IL-12 p40 secretion; and, in addition, IL-4 partially inhibits CD40-induced IL-12 p40 secretion and enhances IL-10-mediated inhibition in an additive fashion. We also investigated the in vivo relevance of this interaction in an experimental model for a Th1-mediated disease, the hapten reagent (TNBS)-induced colitis. The administration of anti-gp39 (CD40L) antibodies during the induction phase of the Th1 response completely prevented IFN-gamma production by CD4 T cells from the intestinal lamina propria and also the clinical and histological evidence of disease. In further studies we showed that the prevention of disease activity was due to an inhibition of IL-12 secretion. Thus, the injection of recombinant IL12 p75 heterodimer into TNBS + anti-gp39-treated mice reversed the effect of anti-gp39 and resulted in severe disease activity. In conclusion, these findings suggest that DCs produce IL-12 in response to CD40 signaling, that a mechanism by which IL-4 may induce Th2 development is by acting with IL-10 to inhibit IL-12 production by DCs, and that the CD40L-CD40 interaction is crucial for the IL-12-dependent priming of Th1 T cells in vivo.
DOI：
10.1172/jci117453
发表时间：
1994-09
期刊：
The Journal of clinical investigation
影响因子：
--
作者：
F. H. Durie;A. Aruffo;J. Ledbetter;K. M. Crassi;W. Green;L. Fast;R. Noelle
通讯作者：
F. H. Durie;A. Aruffo;J. Ledbetter;K. M. Crassi;W. Green;L. Fast;R. Noelle
影响因子：
56.9
作者：
DURIE, FH;FAVA, RA;NOELLE, RJ
通讯作者：
NOELLE, RJ
DOI：
10.1073/pnas.89.14.6550
发表时间：
1992-07-15
影响因子：
11.1
作者：
NOELLE, RJ;ROY, M;ARUFFO, A
通讯作者：
ARUFFO, A