Musicki Korana, Briscoe Helen, Tran Stephen, Britton Warwick J, Saunders Bernadette M
Centenary Institute of Cancer Medicine and Cell Biology, Locked Bag No. 6, Newtown, NSW 2042, Australia.
Infect Immun. 2006 Jun;74(6):3180-9. doi: 10.1128/IAI.02004-05.
The relative contributions of transmembrane tumor necrosis factor (memTNF) and soluble tumor necrosis factor (solTNF) in innate and adaptive immunity are poorly defined. We examined the capacities of wild-type (WT) mice, TNF-/- mice, and memTNF mice, which express only transmembrane TNF, to control primary and secondary Listeria monocytogenes infections. Soluble TNF was not required for induction or maintenance of protective immunity against a low-dose (200-CFU) Listeria infection. In contrast to TNF-/- mice, both WT and memTNF mice cleared the bacilli within 10 days and were fully protected against rechallenge with a lethal infective dose. Furthermore, T cells transferred from immune mice, but not from naïve, WT, and memTNF mice, protected TNF-/- recipients against an otherwise lethal infection. By contrast, infection with a higher dose of Listeria (2,000 CFU) clearly demonstrated that solTNF is required to coordinate an optimal protective inflammatory response. memTNF mice were more susceptible to a high-dose infection, and they exhibited delayed bacterial clearance, increased inflammation, and necrosis in the liver that resulted in 55% mortality. The dysregulated inflammation was accompanied by prolonged elevated expression of mRNAs for several chemokines as well as the macrophage effector molecules inducible nitric oxide synthase and LRG-47 in the livers of memTNF mice but not in the livers of WT mice. These data demonstrated that memTNF is sufficient for establishing protective immunity against a primary low-dose Listeria infection but that solTNF is required for optimal control of cellular inflammation and resistance to a primary high-dose infection. By contrast, memTNF alone is sufficient for resolution of a secondary, high-dose infection and for the transfer of protective immunity with memory T cells.
跨膜肿瘤坏死因子（memTNF）和可溶性肿瘤坏死因子（solTNF）在固有免疫和适应性免疫中的相对作用尚不清楚。我们检测了野生型（WT）小鼠、TNF-/-小鼠和仅表达跨膜TNF的memTNF小鼠控制原发性和继发性单核细胞增生李斯特菌感染的能力。对于低剂量（200 CFU）李斯特菌感染，诱导或维持保护性免疫并不需要可溶性TNF。与TNF-/-小鼠不同，WT小鼠和memTNF小鼠均在10天内清除了杆菌，并对致死性感染剂量的再次攻击具有完全保护作用。此外，从免疫小鼠而非未免疫、WT和memTNF小鼠转移的T细胞可保护TNF-/-受体免受致死性感染。相比之下，用更高剂量的李斯特菌（2000 CFU）感染清楚地表明，需要solTNF来协调最佳的保护性炎症反应。memTNF小鼠对高剂量感染更易感，它们表现出细菌清除延迟、炎症增加以及肝脏坏死，导致55%的死亡率。炎症失调伴随着memTNF小鼠肝脏中几种趋化因子以及巨噬细胞效应分子诱导型一氧化氮合酶和LRG-47的mRNA表达持续升高，而WT小鼠肝脏中则没有这种情况。这些数据表明，memTNF足以建立针对原发性低剂量李斯特菌感染的保护性免疫，但solTNF是最佳控制细胞炎症和抵抗原发性高剂量感染所必需的。相比之下，单独的memTNF足以解决继发性高剂量感染并通过记忆T细胞传递保护性免疫。
