Padigel U M, Perrin P J, Farrell J P
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
J Immunol. 2001 Nov 15;167(10):5874-9. doi: 10.4049/jimmunol.167.10.5874.
CD40-CD40L interactions have been shown to be essential for the production of IL-12 and IFN-gamma and control of L. major infection. In contrast, C57BL/6 mice deficient in CD28 develop a dominant Th1-type response and heal infection. In this study, we investigate the effects of a deficiency in both CD40L and CD28 molecules on the immune response and the course of L. major infection. We compared infection in mice genetically lacking CD40L (CD40L(-/-)), CD28 (CD28(-/-)), or both (CD40L(-/-)CD28(-/-)), and in C57BL/6 mice, all on a resistant background. Although CD40L(-/-) mice failed to control infection, CD28(-/-) and CD40L(-/-)CD28(-/-) mice, as well as C57BL/6 mice, spontaneously resolved their infections. Healing mice had reduced numbers of lesion parasites compared with nonhealing CD40L(-/-) mice. At wk 9 of infection, we detected similar levels of IL-4, IFN-gamma, IL-12p40, and IL-12Rbeta2 mRNA in draining lymph nodes of healing C57BL/6, CD28(-/-), and CD40L(-/-)CD28(-/-) mice, whereas CD40L(-/-) mice had increased mRNA levels for IL-4 but reduced levels for IFN-gamma, IL-12p40, and IL-12Rbeta2. In a separate experiment, blocking of the CD40-CD40L pathway using Ab to CD40L led to an exacerbation of infection in C57BL/6 mice, but had little or no effect on infection in CD28(-/-) mice. Together, these results demonstrate that in the absence of CD28 costimulation, CD40-CD40L interaction is not required for the development of a protective Th1-type response. The expression of IL-12p40, IL-12Rbeta2, and IFN-gamma in CD40L(-/-)CD28(-/-) mice further suggests the presence of an additional stimulus capable of regulating IL-12 and its receptors in absence of CD40-CD40L interactions.
CD40与CD40配体（CD40L）的相互作用已被证明对白细胞介素-12（IL-12）和γ干扰素（IFN-γ）的产生以及对硕大利什曼原虫感染的控制至关重要。相比之下，缺乏CD28的C57BL/6小鼠会产生占主导地位的Th1型反应并治愈感染。在本研究中，我们调查了CD40L和CD28分子双缺陷对免疫反应及硕大利什曼原虫感染进程的影响。我们比较了基因敲除CD40L（CD40L(-/-)）、CD28（CD28(-/-)）或两者（CD40L(-/-)CD28(-/-)）的小鼠以及C57BL/6小鼠（均为抗性背景）的感染情况。尽管CD40L(-/-)小鼠无法控制感染，但CD-28(-/-)小鼠、CD40L(-/-)CD28(-/-)小鼠以及C57BL/6小鼠均自发地清除了感染。与未治愈的CD40L(-/-)小鼠相比，治愈小鼠的病灶寄生虫数量减少。在感染第9周时，我们在治愈的C57BL/6小鼠、CD28(-/-)小鼠和CD40L(-/-)CD28(-/-)小鼠的引流淋巴结中检测到相似水平的IL-4、IFN-γ、IL-12p40和IL-12Rβ2 mRNA，而CD40L(-/-)小鼠的IL-4 mRNA水平升高，但IFN-γ、IL-12p40和IL-12Rβ2的水平降低。在另一项实验中，使用抗CD40L抗体阻断CD40 - CD40L途径会导致C57BL/6小鼠的感染加剧，但对CD28(-/-)小鼠的感染几乎没有影响。总之，这些结果表明，在缺乏CD28共刺激的情况下，产生保护性Th1型反应并不需要CD40 - CD40L相互作用。CD40L(-/-)CD28(-/-)小鼠中IL-12p40、IL-12Rβ2和IFN-γ的表达进一步表明，在缺乏CD40 - CD40L相互作用的情况下，存在一种能够调节IL-12及其受体的额外刺激因素。
