A schistosome-expressed immunomodulatory glycoconjugate expands peritoneal Gr1+ macrophages that suppress naive CD4+ T cell proliferation via an IFN-γ and nitric oxide-dependent mechanism
A schistosome-expressed immunomodulatory glycoconjugate expands peritoneal Gr1+ macrophages that suppress naive CD4+ T cell proliferation via an IFN-γ and nitric oxide-dependent mechanism
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DOI：
10.4049/jimmunol.167.8.4293
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发表时间：
2001-10-15
影响因子：
4.4
通讯作者：
Harn, DA
中科院分区：
文献类型：
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作者：
Atochina, O;Daly-Engel, T;Harn, DA
乳糖-N-岩藻五糖III（LNFPIII）存在于人乳以及驱动Th2型免疫反应的曼氏血吸虫这种蠕虫寄生虫中。当与载体结合时，这种五糖在体内和体外均可驱动Th2型免疫反应。为了进一步了解从Th1到Th2转换的早期事件，我们检测了注射LNFPIII - 葡聚糖后BALB/c和SCID小鼠腹腔细胞群的表型和功能变化。我们发现腹腔注射LNFPIII - 葡聚糖会导致F4/80(+) / CD11b(+)腹腔细胞中Gr1(+)亚群迅速（<20小时）扩增，在未注射或仅注射葡聚糖的小鼠中该亚群占F4/80(+) / CD11b(+)腹腔细胞的18%，而注射LNFPIII - 葡聚糖后可高达75%。在功能上，这些细胞抑制了抗CD3和抗CD28诱导的初始CD4(+) T细胞增殖。LNFPIII - 葡聚糖也会使SCID小鼠中具有功能的Gr1(+)抑制性巨噬细胞扩增，这表明抑制性细胞的扩增和功能不需要T细胞。在BALB/c和SCID小鼠中，这种抑制作用均依赖于NO和干扰素 - γ，因为添加诱导型一氧化氮合酶抑制剂（N - G - 单甲基 - L - 精氨酸）以及抗干扰素 - γ抗体可恢复CD4(+) T细胞在体外的增殖能力。去除Gr1(+)细胞中的F4/80(+)亚群会消除腹腔渗出细胞的抑制活性，这表明这些细胞是巨噬细胞。因此，LNFPIII - 葡聚糖可在原本未免疫的小鼠腹腔中迅速扩增Gr1(+)抑制性巨噬细胞群。这些Gr1(+)细胞以一种依赖NO的机制抑制初始CD4(+) T细胞的增殖，并可能在Th1型向Th2型免疫反应转换中起调节作用。
Lacto-N-fucopentaose III (LNFPIII) is found in human milk and on the Th2 driving helminth parasite Schistosoma mansoni. This pentasaccharide drives Th2-type responses in vivo and in vitro when conjugated to a carrier. In an attempt to further understand early events in Th1 to Th2 switching, we examined phenotypic and functional changes in peritoneal cell populations in BALB/c and SCID mice following LNFPIII-dextran injection. We found that i.p. injection with LNFPIII-dextran resulted in rapid (< 20 h) expansion of the Gr1(+) subpopulation of F4/80(+)/CD11b(+) peritoneal cells, comprising up to 75% of F4/80(+)/CD11b(+) peritoneal cells compared with 18% in uninjected or dextran-injected mice. Functionally, these cells suppressed anti-CD3- and anti-CD28-induced proliferation of naive CD4(+) T cells. LNFPIII-dextran also expanded functional Gr1(+) suppressor macrophages in SCID mice, demonstrating that expansion and function of suppressor cells did not require T cells. Suppression in both BALB/c and SCID mice was NO and IFN-gamma dependent, as addition of inhibitors of inducible NO Synthase (N-G-monomethyl-L-arginine), as well as anti-IFN-gamma Abs, restored the ability of CD4(+) T cells to proliferate in vitro. Depletion of the F4/80(+) subset of Gr1(+) cells eliminated the suppressive activity of peritoneal exudate cells showing that these cells were macrophages. Thus, LNFPIII-dextran rapidly expands the Gr1(+) suppressor macrophage population in the peritoneal cavities of otherwise naive mice. These Gr1(+) cells suppress proliferation of naive CD4(+) T cells in an NO-dependent mechanism, and may play a regulatory role in the switching of Th1(-) to Th2-type responses.