Soluble TNFRp75 regulates host protective immunity against Mycobacterium tuberculosis
Soluble TNFRp75 regulates host protective immunity against Mycobacterium tuberculosis
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DOI：
10.1172/jci45005
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发表时间：
2014-04-01
影响因子：
15.9
通讯作者：
Jacobs, Muazzam
中科院分区：
文献类型：
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作者：
Keeton, Roanne;Allie, Nasiema;Jacobs, Muazzam
宿主对结核分枝杆菌感染的保护性免疫的发展关键取决于炎性细胞因子TNF。TNF通过2种受体TNFRp 55和TNFRp 75进行信号传导;然而，TNFRp 75依赖性信号传导在免疫调节中的作用尚不清楚。在这里，我们发现缺乏TNFRp 75的小鼠表现出对M.与WT小鼠相比，结核病感染。TNFRp 75（-/-）小鼠产生了有效的杀菌性肉芽肿，并表现出激活的DC的肺募集增加。此外，IL-12 p40依赖性DC向感染TNFRp 75（-/-）小鼠的肺引流LN的迁移显著高于在WT M中观察到的。结核病感染的动物，并与激活的M.结核特异性IFN-γ表达CD 4（+）T细胞。在WT小鼠中，TNFRp 75脱落与显著降低的生物活性TNF水平和IL-12 p40表达相关。M.中TNFRp 75的中和结核病感染的WT BM衍生的DC（BMDC）将生物活性TNF和IL-12 p40的产生增加到与TNFRp 75（-/-）BMDC产生的水平相当。将外源性TNFRp 75添加到用M.结核病减少IL-12 p40合成，证明TNFRp 75脱落调节DC活化。这些数据表明，TNFRp 75脱落降低了保护性免疫功能，降低了宿主的抵抗力和存活率;因此，靶向TNFRp 75可能有利于改善疾病结局。
Development of host protective immunity against Mycobacterium tuberculosis infection is critically dependent on the inflammatory cytokine TNF. TNF signals through 2 receptors, TNFRp55 and TNFRp75; however, the role of TNFRp75-dependent signaling in immune regulation is poorly defined. Here we found that mice lacking TNFRp75 exhibit greater control of M. tuberculosis infection compared with WT mice. TNFRp75(-/-) mice developed effective bactericidal granulomas and demonstrated increased pulmonary recruitment-of activated DCs. Moreover, IL-12p40-dependent migration of DCs to lung draining LNs of infected TNFRp75(-/-) mice was substantially higher than that observed in WT M. tuberculosis-infected animals and was associated with enhanced frequencies of activated M. tuberculosis-specific IFN-gamma-expressing CD4(+) T cells. In WT mice, TNFRp75 shedding correlated with markedly reduced bioactive TNF levels and IL-12p40 expression. Neutralization of TNFRp75 in M. tuberculosis-infected WT BM-derived DCs (BMDCs) increased production of bioactive TNF and IL-12p40 to a level equivalent to that produced by TNFRp75(-/-) BMDCs. Addition of exogenous TNFRp75 to TNFRp75(-/-) BMDCs infected with M. tuberculosis decreased IL-12p40 synthesis, demonstrating that TNFRp75 shedding regulates DC activation. These data indicate that TNFRp75 shedding dowmnodulates protective immune function and reduces host resistance and survival; therefore, targeting TNFRp75 may be beneficial for improving disease outcome.