Rapid rebound of the Treg compartment in DEREG mice limits the impact of Treg depletion on mycobacterial burden, but prevents autoimmunity.
Rapid rebound of the Treg compartment in DEREG mice limits the impact of Treg depletion on mycobacterial burden, but prevents autoimmunity.
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DOI：
10.1371/journal.pone.0102804
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Sparwasser T
中科院分区：
文献类型：
--
作者：
Berod L;Stüve P;Varela F;Behrends J;Swallow M;Kruse F;Krull F;Ghorbani P;Mayer CT;Hölscher C;Sparwasser T
开发有效的结核病疫苗是本世纪的主要医学挑战之一。牛分枝杆菌卡介苗（BCG）是目前唯一可用的疫苗，在预防儿童播散性结核病方面最有效，但对成人最常见的肺结核病的保护作用不同。这种疗效差的原因尚不完全清楚，但有证据表明可能涉及T调节细胞（TCFs）。类似地，Tb与在感染Tb的患者中观察到的免疫抑制相关，因此被认为在病原体持续存在中起作用。因此，Treg耗竭被假定为增强M.牛卡介苗接种，而另一方面，作为一种治疗方法，在慢性结核感染。然而，由于Tcl 4在控制自身免疫性炎症中起关键作用，因此Tcl 4的消除也可能导致过度炎症免疫应答的危险。因此，了解结核杆菌感染期间Treg的动态和功能对于评估Treg消耗作为医疗选择的潜力至关重要。为了解决这个问题，我们在感染M.牛BCG或结核分枝杆菌（Mtb），所述小鼠在FoxP 3基因座的控制下表达白喉毒素（DT）受体，从而允许选择性耗尽FoxP 3 + TbR。我们的研究结果表明，耗尽后，Treg生态位迅速重新填充的DT-不敏感的T细胞（diT细胞）的人口和细菌负荷保持不变。相反，DEREG × FoxP 3GFP小鼠中的TcB反弹受损改善了病原体负荷，但伴随着有害的自身免疫性炎症。因此，我们的研究提供了原理证明，尽管高度的Treg耗竭可能有助于控制分枝杆菌感染，但它具有自身免疫的风险。
The development of an effective vaccine against tuberculosis (Tb) represents one of the major medical challenges of this century. Mycobacterium bovis Bacille Calmette-Guerin (BCG), the only vaccine available at present, is mostly effective at preventing disseminated Tb in children, but shows variable protection against pulmonary Tb, the most common form in adults. The reasons for this poor efficacy are not completely understood, but there is evidence that T regulatory cells (Tregs) might be involved. Similarly, Tregs have been associated with the immunosuppression observed in patients infected with Tb and are therefore believed to play a role in pathogen persistence. Thus, Treg depletion has been postulated as a novel strategy to potentiate M. bovis BCG vaccination on one side, while on the other, employed as a therapeutic approach during chronic Tb infection. Yet since Tregs are critically involved in controlling autoimmune inflammation, elimination of Tregs may therefore also incur the danger of an excessive inflammatory immune response. Thus, understanding the dynamics and function of Tregs during mycobacterial infection is crucial to evaluate the potential of Treg depletion as a medical option. To address this, we depleted Tregs after infection with M. bovis BCG or Mycobacterium tuberculosis (Mtb) using DEREG mice, which express the diphtheria toxin (DT) receptor under the control of the FoxP3 locus, thereby allowing the selective depletion of FoxP3+ Tregs. Our results show that after depletion, the Treg niche is rapidly refilled by a population of DT-insensitive Tregs (diTregs) and bacterial load remains unchanged. On the contrary, impaired rebound of Tregs in DEREG × FoxP3GFP mice improves pathogen burden, but is accompanied by detrimental autoimmune inflammation. Therefore, our study provides the proof-of-principle that, although a high degree of Treg depletion may contribute to the control of mycobacterial infection, it carries the risk of autoimmunity.
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影响因子：
5.5
作者：
Ho, Peiying;Wei, Xing;Seah, Geok Teng
通讯作者：
Seah, Geok Teng
影响因子：
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作者：
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Mascart, Francoise
影响因子：
32.4
作者：
Fontenot, JD;Rasmussen, JP;Rudensky, AY
通讯作者：
Rudensky, AY
DOI：
10.4049/jimmunol.1101649
发表时间：
2011-09-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Kastenmuller W;Gasteiger G;Subramanian N;Sparwasser T;Busch DH;Belkaid Y;Drexler I;Germain RN
通讯作者：
Germain RN
DOI：
10.4049/jimmunol.1200061
发表时间：
2013-01-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Green AM;Difazio R;Flynn JL
通讯作者：
Flynn JL