Kelsall B L, Stüber E, Neurath M, Strober W
Mucosal Immunity Section, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Ann N Y Acad Sci. 1996 Oct 31;795:116-26. doi: 10.1111/j.1749-6632.1996.tb52660.x.
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.
最近的研究表明，在小鼠II型胶原诱导的关节炎模型、急性半同种异体移植物抗宿主病以及同种异体特异性CTL反应（即被认为由Th1型T细胞介导的反应）中，用抗gp39抗体处理小鼠会损害T细胞功能。另一方面，抗gp39抗体的施用并不影响Th2 T细胞反应，这表明CD40-CD40L相互作用对Th1细胞发育比Th2细胞发育更为关键。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，对人单核细胞上CD40的刺激会导致IL-12的产生，这表明表达CD40L的活化T细胞可能直接诱导抗原呈递细胞产生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。我们在一个能够精确控制细胞因子浓度的体外系统中研究了CD40-CD40L相互作用在DC产生IL-12过程中是否重要。最初我们发现，通过表达CD40L的成纤维细胞使CD40交联后，经FACS纯化的小鼠脾脏DC会产生大量的IL-12 p40。然后我们证明，在一个更接近生理状态的系统中，用卵清蛋白（OVA）脉冲处理纯化的DC，然后与来自卵清蛋白T细胞受体转基因小鼠的LECAM-1hi T细胞一起培养，DC也会产生IL-12 p40。最后，我们发现IL-10具有强大的能力来抑制CD40诱导的IL-12 p40分泌；此外，IL-4部分抑制CD40诱导的IL-12 p40分泌，并以累加的方式增强IL-10介导的抑制作用。我们还在一个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在体内的相关性。在Th1反应的诱导阶段给予抗gp39（CD40L）抗体，完全阻止了肠道固有层CD4 T细胞产生IFN-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，疾病活动的预防是由于IL-12分泌的抑制。因此，向TNBS + 抗gp39处理的小鼠注射重组IL12 p75异二聚体可逆转抗gp39的作用，并导致严重的疾病活动。总之，这些发现表明DC对CD40信号作出反应产生IL-12，IL-4诱导Th2细胞发育的一种机制可能是与IL-10共同作用抑制DC产生IL-12，并且CD40L-CD40相互作用对于体内Th1 T细胞依赖IL-12的启动至关重要。
