CD4 T Cell-Derived IFN-γ Plays a Minimal Role in Control of Pulmonary Mycobacterium tuberculosis Infection and Must Be Actively Repressed by PD-1 to Prevent Lethal Disease.
CD4 T Cell-Derived IFN-γ Plays a Minimal Role in Control of Pulmonary Mycobacterium tuberculosis Infection and Must Be Actively Repressed by PD-1 to Prevent Lethal Disease.
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DOI：
10.1371/journal.ppat.1005667
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发表时间：
2016-05
期刊：
影响因子：
6.7
通讯作者：
Barber DL
中科院分区：
文献类型：
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作者：
Sakai S;Kauffman KD;Sallin MA;Sharpe AH;Young HA;Ganusov VV;Barber DL
产生干扰素-γ的CD4T细胞是预防结核分枝杆菌(MTB)感染所必需的，但干扰素-γ对整体CD4T细胞介导的保护作用的程度尚不清楚。此外，在结核分枝杆菌感染中，增加CD4T细胞产生干扰素-γ是否是可取的，目前还不清楚。在这里，我们显示干扰素-γ只占CD4T细胞依赖的累积细菌控制在肺部的前六周的~30%，但在脾中的对照的80%。此外，尽管加强了对脾的控制，但将CD4T细胞产生干扰素-γ的能力提高~2倍会加剧肺部感染，并导致宿主过早死亡。此外，我们还表明，抑制受体PD-1通过防止CD4T细胞产生有害的干扰素-γ而促进宿主对结核分枝杆菌的抵抗力。具体地说，PD-1抑制了CXCR3+KLRG1-CX3CR1-肺归巢CD4T细胞亚群的实质积累和致病性干扰素-γ的产生，否则该亚群介导了对结核分枝杆菌感染的控制。因此，T细胞来源的干扰素-γ在结核分枝杆菌感染中的主要作用是在肺外部位，而CD4T细胞的宿主保护性亚群需要PD-1负调控干扰素-γ的产生，以防止致命的免疫介导的病理。由于缺乏对宿主保护机制的了解，新型结核病疫苗的开发一直受到阻碍。长期以来，一直认为干扰素-γ是CD4T细胞介导的抗结核分枝杆菌感染的主要效应者，但结核分枝杆菌特异性的CD4T细胞在体内产生少量的干扰素-γ，这导致了增加Th1细胞产生干扰素-γ的可能性，从而可能加强对结核分枝杆菌感染的控制。然而，干扰素-γ对CD4T细胞依赖保护的确切贡献以及增加CD4T细胞产生干扰素-γ的结果还没有被评估。在这里，我们显示干扰素-γ在感染的前1.5个月中仅占CD4T细胞介导的肺部细菌负荷累积减少的约30%。此外，我们还发现，增加CD4T细胞人均产生的干扰素-γ会导致宿主的过早死亡。最后，我们发现抑制受体PD-1对CD4T细胞来源的干扰素-γ的抑制对于预防致死性疾病是必不可少的。因此，控制不佳的结核分枝杆菌感染并不是由于干扰素-γ的生产缺陷造成的，选择性地提高它的策略是没有根据的。此外，确定依赖CD4T细胞控制结核分枝杆菌感染的主要机制应该是优先考虑的。
IFN-γ–producing CD4 T cells are required for protection against Mycobacterium tuberculosis (Mtb) infection, but the extent to which IFN-γ contributes to overall CD4 T cell-mediated protection remains unclear. Furthermore, it is not known if increasing IFN-γ production by CD4 T cells is desirable in Mtb infection. Here we show that IFN-γ accounts for only ~30% of CD4 T cell-dependent cumulative bacterial control in the lungs over the first six weeks of infection, but >80% of control in the spleen. Moreover, increasing the IFN-γ–producing capacity of CD4 T cells by ~2 fold exacerbates lung infection and leads to the early death of the host, despite enhancing control in the spleen. In addition, we show that the inhibitory receptor PD-1 facilitates host resistance to Mtb by preventing the detrimental over-production of IFN-γ by CD4 T cells. Specifically, PD-1 suppressed the parenchymal accumulation of and pathogenic IFN-γ production by the CXCR3+KLRG1-CX3CR1- subset of lung-homing CD4 T cells that otherwise mediates control of Mtb infection. Therefore, the primary role for T cell-derived IFN-γ in Mtb infection is at extra-pulmonary sites, and the host-protective subset of CD4 T cells requires negative regulation of IFN-γ production by PD-1 to prevent lethal immune-mediated pathology. The development of novel tuberculosis vaccines has been hindered by the poor understanding of the mechanisms of host-protection. It has been long-held that IFN-γ is the principle effector of CD4 T cell-mediated resistance to Mtb infection, but Mtb-specific CD4 T cells produce low amounts of IFN-γ in vivo, leading to the possibility that increasing IFN-γ production by Th1 cells might enhance control of Mtb infection. However, the precise contribution of IFN-γ to CD4 T cell-dependent protection and the outcome of increasing IFN-γ production by CD4 T cells have not been evaluated. Here we show that IFN-γ accounts for only ~30% of the cumulative CD4 T cell-mediated reduction in lung bacterial loads over the first 1.5 months of infection. Moreover, we find that increasing the per capita production of IFN-γ by CD4 T cells leads to the early death of the host. Lastly, we show that suppression of CD4 T cell-derived IFN-γ by the inhibitory receptor PD-1 is essential to prevent lethal disease. Therefore, poor control Mtb infection does not result from defective production of IFN-γ, and strategies to selectively boost it are unwarranted. Furthermore, identifying the primary mechanisms of CD4 T cell-dependent control of Mtb infection should be a priority.