Tuberculosis presents a global health challenge, and tumour necrosis factor (TNF) signalling is required for host immunity against Mycobacterium tuberculosis (Mtb). TNF receptor shedding, however, compromises effective immunity by reducing bioactive TNF through the formation of inactive complexes. In this study, we first compared the effect of total soluble TNF receptors using a transgenic p55^ΔNS/p75^−/− murine strain on host protection during a low-dose aerosol Mtb H37Rv challenge. We report that the presence of membrane-bound TNFRp55 alone in the absence of TNFRp75 results in superior control of a primary Mtb infection where p55^ΔNS/p75^−/− hyperactive dendritic cells displayed an increased capacity to induce a hyperactive Mtb-specific CD4⁺ T-cell response. p55^ΔNS/p75^−/− dendritic cells expressed a higher frequency of MHCII and increased MFIs for both CD86 and MHCII, while CD4⁺ T cells had higher expression of CD44 and IFN-γ. Next, the relative contributions of soluble TNFRp55 and soluble TNFRp75 to host protection against either primary Mtb infection or during reactivation of latent tuberculosis were delineated by comparing the experimental outcomes of control C57BL/6 mice to transgenic p55^ΔNS/p75^−/−, p55^ΔNS and p75^−/− mouse strains. We found that soluble TNFRp55 is redundant for immune regulation during the chronic stages of a primary Mtb infection. However, TNFRp55 together with soluble TNFRp75 has a crucial role in immune regulation of reactivation of latent tuberculosis.

中文翻译：

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结核分枝杆菌的免疫控制依赖于可溶性 TNFRp55 和可溶性 TNFRp75

结核病是一项全球性的健康挑战，宿主对结核分枝杆菌( Mtb ) 的免疫需要肿瘤坏死因子 (TNF) 信号传导。然而，TNF 受体脱落会通过形成无活性复合物减少具有生物活性的 TNF，从而损害有效免疫。在这项研究中，我们首先比较了使用转基因 p55 ^ΔNS /p75 ^-/-鼠菌株在低剂量气溶胶Mtb H37Rv 攻击期间总可溶性 TNF 受体对宿主保护的影响。我们报告说，在没有 TNFRp75 的情况下，仅存在膜结合 TNFRp55 可以更好地控制原发性Mtb感染，其中 p55 ^ΔNS /p75 ^-/-过度活跃的树突状细胞表现出增强的诱导过度活跃的Mtb特异性 CD4 ⁺ T 细胞反应的能力。p55 ^ΔNS /p75 ^-/-树突状细胞表达更高频率的 MHCII 并增加 CD86 和 MHCII 的 MFI，而 CD4 ⁺ T 细胞具有更高的 CD44 和 IFN-γ 表达。^{接下来，通过比较对照 C57BL/6 小鼠与转基因 p55 ΔNS} /p75 ^-/-、p55 ^ΔNS的实验结果，描述了可溶性 TNFRp55 和可溶性 TNFRp75 对宿主保护免受原发性 Mtb 感染或潜伏性结核病再激活期间的相对贡献。和 p75 ^-/-小鼠品系。我们发现可溶性 TNFRp55 在原发性Mtb感染的慢性阶段对于免疫调节是多余的。然而，TNFRp55 与可溶性 TNFRp75 在潜伏性结核病再激活的免疫调节中起关键作用。