Disruption of Early Tumor Necrosis Factor Alpha Signaling Prevents Classical Activation of Dendritic Cells in Lung-Associated Lymph Nodes and Development of Protective Immunity against Cryptococcal Infection.
Disruption of Early Tumor Necrosis Factor Alpha Signaling Prevents Classical Activation of Dendritic Cells in Lung-Associated Lymph Nodes and Development of Protective Immunity against Cryptococcal Infection.
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DOI：
10.1128/mbio.00510-16
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发表时间：
2016-07-12
期刊：
影响因子：
6.4
通讯作者：
Olszewski MA
中科院分区：
文献类型：
--
作者：
Xu J;Eastman AJ;Flaczyk A;Neal LM;Zhao G;Carolan J;Malachowski AN;Stolberg VR;Yosri M;Chensue SW;Curtis JL;Osterholzer JJ;Olszewski MA
抗肿瘤坏死因子α（抗TNF-α）疗法已越来越多地用于治疗炎症性疾病，并且与侵袭性真菌感染（包括新型隐球菌感染）的风险增加有关。使用隐球菌感染的小鼠模型，我们研究了早期 TNF-α 信号传导破坏导致针对新型隐球菌的非保护性免疫发展的机制。我们发现，在免疫反应的适应性阶段，TNF-α 的瞬时消耗会抑制肺部真菌清除并增强新型隐球菌的肺外传播。 TNF-α 耗尽的小鼠中真菌负荷较高，同时受感染肺部的 Th1 和 Th17 反应明显受损。此外，早期 TNF-α 耗竭还导致 Th17 极化程序的转录启动中断，并随后导致新型隐球菌感染小鼠肺相关淋巴结 (LALN) 中 CD4+ T 细胞中 Th1 基因的上调。在 LALN T 细胞反应出现这些缺陷之前，TNF-α 耗尽的小鼠 LALN 中的树突状细胞 (DC) 的激活发生了从经典激活到替代激活的巨大转变。综上所述，我们的结果表明，早期 TNF-α 信号传导是最佳 DC 激活所必需的，并且 LALN 中 T 细胞的初始 Th17 反应随后发生 Th1 转录预极化，这进一步推动了肺部针对隐球菌感染的保护性免疫的发展。因此，给予抗TNF-α可能会给新获得的真菌感染带来特别更大的风险，这些感染需要产生保护性Th1/Th17反应来遏制和清除。接受抗 TNF-α 治疗的患者对侵袭性真菌感染的易感性增加，这凸显了了解 TNF-α 信号传导在促进针对真菌病原体的保护性免疫方面的细胞效应的必要性。在这里，我们证明早期 TNF-α 信号传导对于新生隐球菌感染小鼠 LALN 中 DC 的经典激活和积累是必需的。随后 Th17 转录启动，随后在 LALN 中进行 Th1 编程，导致产生 γ 干扰素和白细胞介素 17A 的 T 细胞在肺部积聚，并有效清除真菌。在接受抗 TNF-α 治疗的小鼠中，所有这些关键步骤均受到严重损害，这与它们无法清除新型隐球菌的能力一致。这项研究确定了先天免疫系统 (DC) 细胞、新兴 T 细胞反应和细胞因子网络之间的关键相互作用，其中 TNF-α 发挥着核心作用，TNF-α 协调了针对隐球菌感染的免疫保护的发展。这些信息对于帮助开发和了解免疫疗法的潜在副作用非常重要。
Anti-tumor necrosis factor alpha (anti-TNF-α) therapies have been increasingly used to treat inflammatory diseases and are associated with increased risk of invasive fungal infections, including Cryptococcus neoformans infection. Using a mouse model of cryptococcal infection, we investigated the mechanism by which disruption of early TNF-α signaling results in the development of nonprotective immunity against C. neoformans. We found that transient depletion of TNF-α inhibited pulmonary fungal clearance and enhanced extrapulmonary dissemination of C. neoformans during the adaptive phase of the immune response. Higher fungal burdens in TNF-α-depleted mice were accompanied by markedly impaired Th1 and Th17 responses in the infected lungs. Furthermore, early TNF-α depletion also resulted in disrupted transcriptional initiation of the Th17 polarization program and subsequent upregulation of Th1 genes in CD4+ T cells in the lung-associated lymph nodes (LALN) of C. neoformans-infected mice. These defects in LALN T cell responses were preceded by a dramatic shift from a classical toward an alternative activation of dendritic cells (DC) in the LALN of TNF-α-depleted mice. Taken together, our results indicate that early TNF-α signaling is required for optimal DC activation, and the initial Th17 response followed by Th1 transcriptional prepolarization of T cells in the LALN, which further drives the development of protective immunity against cryptococcal infection in the lungs. Thus, administration of anti-TNF-α may introduce a particularly greater risk for newly acquired fungal infections that require generation of protective Th1/Th17 responses for their containment and clearance. Increased susceptibility to invasive fungal infections in patients on anti-TNF-α therapies underlines the need for understanding the cellular effects of TNF-α signaling in promoting protective immunity to fungal pathogens. Here, we demonstrate that early TNF-α signaling is required for classical activation and accumulation of DC in LALN of C. neoformans-infected mice. Subsequent transcriptional initiation of Th17 followed by Th1 programming in LALN results in pulmonary accumulation of gamma interferon- and interleukin-17A-producing T cells and effective fungal clearance. All of these crucial steps are severely impaired in mice that undergo anti-TNF-α treatment, consistent with their inability to clear C. neoformans. This study identified critical interactions between cells of the innate immune system (DC), the emerging T cell responses, and cytokine networks with a central role for TNF-α which orchestrate the development of the immune protection against cryptococcal infection. This information will be important in aiding development and understanding the potential side effects of immunotherapies.