The glucocorticoid-induced tumor necrosis factor receptor-related gene modulates the response to Candida albicans infection
The glucocorticoid-induced tumor necrosis factor receptor-related gene modulates the response to Candida albicans infection
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DOI：
10.1128/iai.73.11.7502-7508.2005
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发表时间：
2005-11-01
影响因子：
3.1
通讯作者：
Riccardi, C
中科院分区：
文献类型：
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作者：
Agostini, M;Cenci, E;Riccardi, C
糖皮质激素诱导的肿瘤坏死因子（TNF）受体相关基因（GITR; TNFRSF 18）调节免疫应答，激活T细胞中的辅助信号，并在CD 4（+）CD 25（+）细胞中高水平表达。其配体（GITRL）在抗原呈递细胞中表达，在那里它能够促进信号传导。我们研究了GITR/GITRL相互作用在GITR敲除（GITR（-/-））小鼠中播散性念珠菌病期间的作用。与GITR（+/+）小鼠相比，GITR-/-小鼠存活时间更长，肾脏和大脑中的酵母菌负荷显著降低。由于真菌的保护性免疫是由抗原特异性辅助性T细胞（Th）1介导的，我们研究了感染后的体外细胞因子产生。与GITR（+/+）小鼠相比，GITR-/-小鼠的CD 4（+）T细胞表现出更有效的Th 1极化，如白细胞介素-（IL-）4和IL-10的产生减少2至3倍以及γ干扰素的产生增加4至5倍所示。这种效应不是由于感染小鼠淋巴细胞和树突状细胞（DC）亚群的差异所证明的细胞计数研究。为了验证DC活性是否受到不同的调节，将DC与CD 4（+）T细胞在热灭活的白色念珠菌存在下共培养。与GITR（+/+）CD 4 + CD 25+细胞共培养的DC产生的IL-12的量低于与GITR（-/-）CD 4 + CD 25 + T细胞共培养的DC。这些结果表明，GITR通过负调节IL-12的产生和促进CD 4 + T细胞向Th 2的极化来调节对系统性念珠菌病的易感性，这与另一个TNF受体超家族成员OX 40类似。
The glucocorticoid-induced tumor necrosis factor (TNF) receptor-related gene (GITR; TNFRSF18) modulates immune response activating coaccessory signals in T cells and is expressed at high levels in CD4(+)CD25(+) cells. Its ligand (GITRL) is expressed in antigen-presenting cells, where it is capable of promoting signaling. We investigated the role of GITR/GITRL interaction during disseminated candidiasis in GITR knockout (GITR(-/-)) mice. GITR-/- mice survived longer and had a significantly decreased yeast load in kidneys and brain compared to GITR(+/+) mice. Since protective immunity to the fungus is mediated by antigen-specific T helper (Th) 1 cells, we studied in vitro cytokine production following infection. CD4(+) T cells of GITR-/- mice demonstrated a more efficient Th1 polarization as suggested by a two- to threefold decreased production of interleukin- (IL-)4 and IL-10 and a four- to fivefold increased production of gamma interferon compared to GITR(+/+) mice. This effect was not due to differences in lymphocyte and dendritic cell (DC) subpopulations in infected mice as demonstrated by How cytometric studies. To verify whether DC activity was differently modulated, DCs were cocultured with CD4(+) T cells in the presence of heat-inactivated Candida albicans. DCs, cocultured with GITR(+/+) CD4+CD25+ cells produced a lower amount of IL-12 than DCs cocultured with GITR(-/-) CD4+CD25+ T cells. These results suggest that GITR regulates susceptibility to systemic candidiasis by negatively modulating IL-12 production and promoting polarization of CD4+ T cells towards Th2 by analogy with OX40, another TNF receptor superfamily member.