Role of Granulocyte-Macrophage Colony-Stimulating Factor Production by T Cells during Mycobacterium tuberculosis Infection.
Role of Granulocyte-Macrophage Colony-Stimulating Factor Production by T Cells during Mycobacterium tuberculosis Infection.
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DOI：
10.1128/mbio.01514-17
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发表时间：
2017-10-24
期刊：
影响因子：
6.4
通讯作者：
Behar SM
中科院分区：
文献类型：
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作者：
Rothchild AC;Stowell B;Goyal G;Nunes-Alves C;Yang Q;Papavinasasundaram K;Sassetti CM;Dranoff G;Chen X;Lee J;Behar SM
粒细胞-巨噬细胞集落刺激因子（GM-CSF - / -）缺乏的小鼠对结核分枝杆菌感染高度敏感，临床数据表明，抗GM-CSF中和抗体可导致健康人群对结核病的易感性增加。GM-CSF激活人和小鼠巨噬细胞抑制细胞内结核分枝杆菌生长。我们之前已经证明iNKT细胞产生的GM-CSF抑制结核分枝杆菌的生长。然而，T细胞来源的GM-CSF在感染过程中的更普遍作用尚未确定，GM-CSF如何激活巨噬细胞抑制细菌生长尚不清楚。在这里，我们证明，除了非常规T细胞，常规T细胞也产生GM-CSF结核分枝杆菌感染。在感染早期，非常规iNKT细胞和γδ T细胞是GM-CSF的主要来源，随后随着感染的进展，常规CD4+ T细胞承担了这一作用。在感染者的外周血中也检测到产生GM-CSF的结核分枝杆菌特异性T细胞。在非造血产生GM-CSF不足的情况下，T细胞产生GM-CSF具有保护作用，是控制结核分枝杆菌感染所必需的。然而，在GM-CSF由其他细胞类型产生的情况下，GM-CSF不需要T细胞介导的保护。最后，通过体外巨噬细胞感染模型，我们证明GM-CSF抑制结核分枝杆菌生长需要过氧化物酶体增殖物激活受体γ (PPARγ)的表达。因此，我们确定GM-CSF的产生是一种新的T细胞效应功能。这些发现表明，增加T细胞产生GM-CSF的策略可以增强宿主对结核分枝杆菌的抵抗力。结核分枝杆菌是导致结核病的细菌，结核病是世界上任何感染导致死亡的主要原因。T细胞是结核分枝杆菌免疫反应的关键组成部分。虽然γ干扰素（IFN-γ）是T细胞在感染过程中的关键效应功能，但一项失败的IIb期临床试验和其他研究表明，仅产生IFN-γ并不足以控制结核分枝杆菌。在这项研究中，我们证明了CD4+、CD8+和非常规T细胞在小鼠和被感染人的外周血中结核分枝杆菌感染期间产生GM-CSF。在缺乏其他GM-CSF来源的情况下，T细胞产生GM-CSF具有保护作用，是控制感染所必需的。GM-CSF激活巨噬细胞以限制细菌生长需要宿主表达转录因子PPARγ。鉴定GM-CSF的产生作为T细胞效应功能可能为未来的宿主定向治疗或疫苗设计提供信息。
Mice deficient for granulocyte-macrophage colony-stimulating factor (GM-CSF−/−) are highly susceptible to infection with Mycobacterium tuberculosis, and clinical data have shown that anti-GM-CSF neutralizing antibodies can lead to increased susceptibility to tuberculosis in otherwise healthy people. GM-CSF activates human and murine macrophages to inhibit intracellular M. tuberculosis growth. We have previously shown that GM-CSF produced by iNKT cells inhibits growth of M. tuberculosis. However, the more general role of T cell-derived GM-CSF during infection has not been defined and how GM-CSF activates macrophages to inhibit bacterial growth is unknown. Here we demonstrate that, in addition to nonconventional T cells, conventional T cells also produce GM-CSF during M. tuberculosis infection. Early during infection, nonconventional iNKT cells and γδ T cells are the main source of GM-CSF, a role subsequently assumed by conventional CD4+ T cells as the infection progresses. M. tuberculosis-specific T cells producing GM-CSF are also detected in the peripheral blood of infected people. Under conditions where nonhematopoietic production of GM-CSF is deficient, T cell production of GM-CSF is protective and required for control of M. tuberculosis infection. However, GM-CSF is not required for T cell-mediated protection in settings where GM-CSF is produced by other cell types. Finally, using an in vitro macrophage infection model, we demonstrate that GM-CSF inhibition of M. tuberculosis growth requires the expression of peroxisome proliferator-activated receptor gamma (PPARγ). Thus, we identified GM-CSF production as a novel T cell effector function. These findings suggest that a strategy augmenting T cell production of GM-CSF could enhance host resistance against M. tuberculosis. Mycobacterium tuberculosis is the bacterium that causes tuberculosis, the leading cause of death by any infection worldwide. T cells are critical components of the immune response to Mycobacterium tuberculosis. While gamma interferon (IFN-γ) is a key effector function of T cells during infection, a failed phase IIb clinical trial and other studies have revealed that IFN-γ production alone is not sufficient to control M. tuberculosis. In this study, we demonstrate that CD4+, CD8+, and nonconventional T cells produce GM-CSF during Mycobacterium tuberculosis infection in mice and in the peripheral blood of infected humans. Under conditions where other sources of GM-CSF are absent, T cell production of GM-CSF is protective and is required for control of infection. GM-CSF activation of macrophages to limit bacterial growth requires host expression of the transcription factor PPARγ. The identification of GM-CSF production as a T cell effector function may inform future host-directed therapy or vaccine designs.