Leishmania major Phosphoglycans Influence the Host Early Immune Response by Modulating Dendritic Cell Functions
Leishmania major Phosphoglycans Influence the Host Early Immune Response by Modulating Dendritic Cell Functions
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DOI：
10.1128/iai.01447-08
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发表时间：
2009-08-01
影响因子：
3.1
通讯作者：
Uzonna, Jude E.
中科院分区：
文献类型：
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作者：
Liu, Dong;Kebaier, Chahnaz;Uzonna, Jude E.
利什曼原虫糖结合分子包括磷聚糖(PGs)和脂磷聚糖(LPG)在宿主细胞反应中的确切作用尚不清楚。在这里，我们研究了同时缺乏PGs和LPG的主要利什曼原虫LPG2缺失突变体(lpg2(-))与树突状细胞(DC)的相互作用以及随后感染小鼠的早期免疫反应。令人惊讶的是，在体外和体内，缺乏磷酸多糖并没有影响DC上主要组织相容性复合体II类(MHC II)、CD40、CD80和CD86的表达模式。然而，lpg2(-)L.main在体外诱导感染的骨髓来源的DC(BMDCs)产生的IL-12p40显著高于野生型(WT)寄生虫。此外，lpg2(-)突变感染小鼠的淋巴引流细胞产生IL-12p40的能力高于WT L.重型感染小鼠。在模型抗原呈递实验中，来自lpg2(-)突变感染小鼠的DC比来自WT感染小鼠的DC诱导更多的利什曼原虫特异性T细胞产生的干扰素和IL-2。从感染了lpg2(-)寄生虫的小鼠身上分离出的淋巴细胞产生类似水平的干扰素-γ，但明显低于WT对照组。在另一个缺乏高尔基UDP-半乳糖转运体(lpg5A(-)lpg5B(-))的普通PG缺陷型突变体中也可以看到IL-4的产生减少，但lpg1(-)突变体仅缺乏LPG，因此PGs通常与IL-4的产生减少有关。因此，利什曼原虫PGs通过调节DC功能，抑制抗原提呈，促进早期IL-4应答，从而影响宿主早期免疫应答，它们的缺失可能影响Th1/Th2应答之间的平衡。
The precise role of Leishmania glycoconjugate molecules including phosphoglycans (PGs) and lipophosphoglycan (LPG) on host cellular responses is still poorly defined. Here, we investigated the interaction of Leishmania major LPG2 null mutant (lpg2(-)), which lacks both PGs and LPG, with dendritic cells (DCs) and the subsequent early immune response in infected mice. Surprisingly, the absence of phosphoglycans did not influence expression pattern of major histocompatibility complex class II (MHC II), CD40, CD80, and CD86 on DCs in vitro and in vivo. However, lpg2(-) L. major induced significantly higher production of interleukin12p40 (IL-12p40) by infected bone marrow-derived DCs (BMDCs) than wild-type (WT) parasites in vitro. Furthermore, the production of IL-12p40 by draining lymph node cells from lpg2(-) mutant-infected mice was higher than those from WT L. major-infected mice. In model antigen presentation experiments, DCs from lpg2(-) mutant-infected mice induced more gamma interferon (IFN-gamma) and IL-2 production by Leishmania-specific T cells than those from WT-infected mice. Lymphocytes isolated from mice infected for 3 days with lpg2(-) parasites produce similar levels of IFN-gamma, but significantly less IL-4 and IL-10 than WT controls. Decreased IL-4 production was also seen in another general PG-deficient mutant lacking the Golgi UDP-galactose transporters (lpg5A(-) lpg5B(-)), but not with the lpg1(-) mutant lacking only LPG, thereby implicating PGs generally in the reduction of IL-4 production. Thus, Leishmania PGs influence host early immune response by modulating DC functions in a way that inhibits antigen presentation and promotes early IL-4 response, and their absence may impact the balance between Th1 and Th2 responses.