Regulatory T cell suppressive potency dictates the balance between bacterial proliferation and clearance during persistent Salmonella infection.
Regulatory T cell suppressive potency dictates the balance between bacterial proliferation and clearance during persistent Salmonella infection.
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DOI：
10.1371/journal.ppat.1001043
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发表时间：
2010-08-12
期刊：
影响因子：
6.7
通讯作者：
Way SS
中科院分区：
文献类型：
--
作者：
Johanns TM;Ertelt JM;Rowe JH;Way SS
持续感染的发病机制取决于相反的免疫激活和抑制信号之间的平衡。在此，使用剧毒沙门氏菌来探索表达 Foxp3 的调节性 T 细胞在决定持续性细菌感染的自然进展中的作用和潜在重要性。确定了持续性沙门氏菌感染的两个不同阶段。在感染后的前 3-4 周内，细菌负荷逐渐增加与效应 T 细胞激活延迟相关。相反，在感染后的较晚时间点，细菌负荷的减少与效应 T 细胞的强劲激活相关。使用 Foxp3 GFP 报告小鼠离体分离调节性 T 细胞，我们证明早期和晚期时间点之间感染节奏的二分法与 Foxp3+ Treg 抑制效力的急剧变化直接平行。在使用 Foxp3 DTR 小鼠的补充实验中，通过枚举持续性沙门氏菌感染期间早期和晚期时间点调节性 T 细胞消融对细菌负荷和效应 T 细胞激活的相对影响，验证了 Treg 抑制效力的这些变化对感染结果的重要性。此外，CTLA-4的Treg表达与抑制效力的变化直接平行，并且Treg消融的相对效果可以在很大程度上通过CTLA-4体内阻断来概括。总之，这些结果表明 Treg 抑制效力的动态调节决定了持续细菌感染的过程。免疫激活和抑制之间的平衡受到复杂控制，从而实现宿主对感染的最佳防御，同时最大限度地减少免疫介导对宿主组织的附带损害。尽管调节性 T 细胞在维持这种平衡方面发挥着关键作用，但它们在持续感染自然进展过程中控制免疫细胞激活动态变化的作用尚不清楚。在此，我们使用代表人类伤寒的持续性沙门氏菌感染模型探讨了调节性 T 细胞在控制感染节奏中的相对重要性。感染后早期，当细菌负荷逐渐增加时，保护性免疫成分的激活被延迟，这与调节性 T 细胞抑制效力的增加相一致。相反，在感染后期，当细菌负荷减少时，保护性免疫成分被高度激活，调节性 T 细胞抑制效力显着减弱。此外，持续性沙门氏菌感染的速度是由调节性T细胞控制的，因为在感染后早期，当这些细胞的抑制效力增强时，这些细胞的消融会加速细菌的根除，而稍后当其抑制效力降低时，这些细胞的消融则不会产生明显的影响。因此，调节性 T 细胞抑制控制着沙门氏菌持续感染的速度。
The pathogenesis of persistent infection is dictated by the balance between opposing immune activation and suppression signals. Herein, virulent Salmonella was used to explore the role and potential importance of Foxp3-expressing regulatory T cells in dictating the natural progression of persistent bacterial infection. Two distinct phases of persistent Salmonella infection are identified. In the first 3–4 weeks after infection, progressively increasing bacterial burden was associated with delayed effector T cell activation. Reciprocally, at later time points after infection, reductions in bacterial burden were associated with robust effector T cell activation. Using Foxp3 GFP reporter mice for ex vivo isolation of regulatory T cells, we demonstrate that the dichotomy in infection tempo between early and late time points is directly paralleled by drastic changes in Foxp3+ Treg suppressive potency. In complementary experiments using Foxp3 DTR mice, the significance of these shifts in Treg suppressive potency on infection outcome was verified by enumerating the relative impacts of regulatory T cell ablation on bacterial burden and effector T cell activation at early and late time points during persistent Salmonella infection. Moreover, Treg expression of CTLA-4 directly paralleled changes in suppressive potency, and the relative effects of Treg ablation could be largely recapitulated by CTLA-4 in vivo blockade. Together, these results demonstrate that dynamic regulation of Treg suppressive potency dictates the course of persistent bacterial infection. The balance between immune activation and suppression is intricately controlled allowing optimal host defense against infection, while simultaneously minimizing collateral immune-mediated damage to host tissues. Although regulatory T cells have been implicated to play critical roles in sustaining this balance, their role in controlling the dynamic changes in immune cell activation during the natural progression of persistent infection are undefined. Herein, we explored the relative importance of regulatory T cells in controlling infection tempo using a model of persistent Salmonella infection representative of human typhoid. Early after infection when the bacterial burden is progressively increasing, the activation of protective immune components is delayed, and this coincides with increased regulatory T cell suppressive potency. Conversely, later during infection when reductions in bacterial burden occur, protective immune components are highly activated and regulatory T cell suppressive potency is markedly diminished. Moreover, the tempo of persistent Salmonella infection is controlled by regulatory T cells because ablation of these cells early after infection when their suppressive potency is increased accelerates bacterial eradication, while their ablation later when their suppressive potency is reduced causes no significant effects. Thus, regulatory T cell suppression controls the tempo of persistent Salmonella infection.
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