Prina Eric, Abdi Sofiane Zaki, Lebastard Maï, Perret Emmanuelle, Winter Nathalie, Antoine Jean-Claude
Unité d'Immunophysiologie et Parasitisme Intracellulaire, Institut Pasteur, Paris, France.
J Cell Sci. 2004 Jan 15;117(Pt 2):315-25. doi: 10.1242/jcs.00860. Epub 2003 Dec 2.
In their mammalian hosts, Leishmania are obligate intracellular parasites that mainly reside in macrophages. They are also phagocytosed by dendritic cells (DCs), which play decisive roles in the induction and shaping of T cell-dependent immune responses. Little is known about the role of DCs in the Leishmania life cycle. Here, we examined the ability of mouse bone marrow-derived DCs to serve as hosts for L. amazonensis. Both infective stages of Leishmania (metacyclic promastigotes and amastigotes) could be phagocytosed by DCs, regardless of whether they had previously been experimentally opsonized with either the complement C3 component or specific antibodies. Parasites could survive and even multiply in these cells for at least 72 hours, within parasitophorous vacuoles displaying phagolysosomal characteristics and MHC class II and H-2M molecules. We then studied the degree of maturation reached by infected DCs according to the parasite stage internalised and the type of opsonin used. The cell surface expression of CD24, CD40, CD54, CD80, CD86, OX40L and MHC class II molecules was barely altered following infection with unopsonized promastigotes or amastigotes from nude mice or with C3-coated promastigotes. Even 69 hours post-phagocytosis, a large proportion of infected DCs remained phenotypically immature. In contrast, internalisation of antibody-opsonized promastigotes or amastigotes induced DCs to mature rapidly, as shown by the over-expression of costimulatory, adhesion and MHC class II molecules. Thus, in the absence of specific antibodies (e.g. shortly after infecting naive mammals), infected DCs may remain immature or semi-mature, meaning that they are unable to elicit an efficient anti-Leishmania T cell response. Absence of DC maturation or delayed/incomplete DC maturation could thus be beneficial for the parasites, allowing their establishment and amplification before the onset of immune responses.
在其哺乳动物宿主中，利什曼原虫是专性细胞内寄生虫，主要寄居于巨噬细胞内。它们也会被树突状细胞（DC）吞噬，而树突状细胞在T细胞依赖性免疫反应的诱导和形成中起决定性作用。关于树突状细胞在利什曼原虫生命周期中的作用，人们了解甚少。在此，我们研究了小鼠骨髓来源的树突状细胞作为亚马逊利什曼原虫宿主的能力。利什曼原虫的两个感染阶段（循环前鞭毛体和无鞭毛体）均可被树突状细胞吞噬，无论这些树突状细胞此前是否用补体C3成分或特异性抗体进行过实验性调理。寄生虫能够在这些细胞内存活甚至繁殖至少72小时，寄生泡呈现吞噬溶酶体特征，并含有MHC II类分子和H-2M分子。然后，我们根据内化的寄生虫阶段和所用调理素的类型，研究了被感染树突状细胞的成熟程度。用未调理的前鞭毛体或来自裸鼠的无鞭毛体感染，或用C3包被的前鞭毛体感染后，CD24、CD40、CD54、CD80、CD86、OX40L和MHC II类分子的细胞表面表达几乎没有改变。即使在吞噬后69小时，很大一部分被感染的树突状细胞在表型上仍未成熟。相比之下，抗体调理的前鞭毛体或无鞭毛体的内化会诱导树突状细胞迅速成熟，共刺激分子、黏附分子和MHC II类分子的过度表达即表明了这一点。因此，在缺乏特异性抗体的情况下（例如在感染未接触过病原体的哺乳动物后不久），被感染的树突状细胞可能仍处于未成熟或半成熟状态，这意味着它们无法引发有效的抗利什曼原虫T细胞反应。因此，树突状细胞未成熟或延迟/不完全成熟可能对寄生虫有利，使它们能够在免疫反应开始之前建立并扩增。
