IFN-γ-independent control of M. tuberculosis requires CD4 T cell-derived GM-CSF and activation of HIF-1α.
IFN-γ-independent control of M. tuberculosis requires CD4 T cell-derived GM-CSF and activation of HIF-1α.
复制标题
IFN-γ非依赖性M.结核病需要CD 4 T细胞来源的GM-CSF和HIF-1α的激活。
DOI：
10.1371/journal.ppat.1010721
复制
发表时间：
2022-07
期刊：
影响因子：
6.7
通讯作者：
中科院分区：
文献类型：
--
作者：
目前流行的结核病保护性免疫模式是CD4T细胞产生细胞因子干扰素-γ，激活感染巨噬细胞的杀菌机制。虽然在体内已经证明了基于干扰素-γ非依赖性的CD4T细胞控制结核分枝杆菌感染，但目前尚不清楚在缺乏干扰素-γ的情况下，CD4T细胞是否能够直接激活巨噬细胞来控制感染。我们建立了从感染小鼠肺中分离的CD4T细胞与结核分枝杆菌感染的小鼠骨髓来源的巨噬细胞(BMDM)共培养模型，以研究CD4依赖控制感染的机制。我们发现，即使在没有干扰素-γ信号的情况下，CD4T细胞也可以驱动巨噬细胞激活、M1极化和感染控制。这种不依赖干扰素-γ的感染控制需要激活转录因子HIF-1α，并在感染的巨噬细胞中转变为有氧糖酵解。虽然干扰素-α刺激后的HIF-1γ激活需要一氧化氮，但在没有干扰素-α的情况下，HIF-1γ介导的控制是一氧化氮不依赖的，这表明在感染过程中有不同的途径可以激活HIF-1α。我们发现CD4T细胞来源的GM-CSF对于BMDM的干扰素-γ非依赖性控制是必需的，但重组GM-CSF不足以控制BMDM或肺泡巨噬细胞的感染，也不能挽救缺乏GM-CSF的T细胞的控制。相反，重组GM-CSF控制巨噬细胞的感染，诱导脂滴的生物生成，也需要HIF-1α来控制。这些结果促进了我们对CD4T细胞介导的抗结核分支杆菌免疫的理解，揭示了不同类型巨噬细胞在免疫激活方面的重要差异，并勾勒出了HIF-1α激活的新机制。我们建立了以前未知的GM-CSF和HIF-1α之间的功能联系，并提供了CD4T细胞来源的GM-CSF是一种强大的杀菌效应的证据。CD4T细胞对细菌病原体结核分枝杆菌的免疫控制是必不可少的，部分原因是CD4T细胞产生细胞因子干扰素-γ，激活受感染巨噬细胞的抗菌功能。最近的证据表明，CD4T细胞在结核分枝杆菌的免疫应答中发挥着干扰素-γ非依赖性的作用，但干扰素-γ非依赖性的控制机制仍然不清楚。在这里，我们表明，与干扰素-γ介导的控制一样，干扰素-γ非依赖性控制需要转录因子HIF-1α。低氧诱导因子-1α通过不同的信号通路被激活，并在干扰素-γ介导和非干扰素-γ非依赖的CD4T细胞刺激后介导不同的效应，使低氧诱导因子-1α成为控制巨噬细胞中结核分枝杆菌的关键信号节点。此外，我们还表明，细胞因子GM-CSFCD4T细胞的产生是干扰素-γ非依赖性调控所必需的，而GM-CSF介导的调控需要HIF-1α。这些发现描绘了一条新的、非干扰素-γ依赖的途径，用于CD4T细胞介导的控制，该途径始于GM-CSF的产生，并导致HIF-1α激活以限制感染的巨噬细胞中的结核分枝杆菌。我们对CD4T细胞介导的结核分枝杆菌控制的了解的进展将有助于指导针对这种重要的全球病原体的新的和改进的疫苗的开发。
The prevailing model of protective immunity to tuberculosis is that CD4 T cells produce the cytokine IFN-γ to activate bactericidal mechanisms in infected macrophages. Although IFN-γ-independent CD4 T cell based control of M. tuberculosis infection has been demonstrated in vivo it is unclear whether CD4 T cells are capable of directly activating macrophages to control infection in the absence of IFN-γ. We developed a co-culture model using CD4 T cells isolated from the lungs of infected mice and M. tuberculosis-infected murine bone marrow-derived macrophages (BMDMs) to investigate mechanisms of CD4 dependent control of infection. We found that even in the absence of IFN-γ signaling, CD4 T cells drive macrophage activation, M1 polarization, and control of infection. This IFN-γ-independent control of infection requires activation of the transcription factor HIF-1α and a shift to aerobic glycolysis in infected macrophages. While HIF-1α activation following IFN-γ stimulation requires nitric oxide, HIF-1α-mediated control in the absence of IFN-γ is nitric oxide-independent, indicating that distinct pathways can activate HIF-1α during infection. We show that CD4 T cell-derived GM-CSF is required for IFN-γ-independent control in BMDMs, but that recombinant GM-CSF is insufficient to control infection in BMDMs or alveolar macrophages and does not rescue the absence of control by GM-CSF-deficient T cells. In contrast, recombinant GM-CSF controls infection in peritoneal macrophages, induces lipid droplet biogenesis, and also requires HIF-1α for control. These results advance our understanding of CD4 T cell-mediated immunity to M. tuberculosis, reveal important differences in immune activation of distinct macrophage types, and outline a novel mechanism for the activation of HIF-1α. We establish a previously unknown functional link between GM-CSF and HIF-1α and provide evidence that CD4 T cell-derived GM-CSF is a potent bactericidal effector. CD4 T cells are essential for immune control of the bacterial pathogen Mycobacterium tuberculosis, in part due to CD4 T cell production of the cytokine IFN-γ which activates antimicrobial functions in infected macrophages. Recent evidence points to an IFN-γ-independent role for CD4 T cells during the immune response to M. tuberculosis, but mechanisms of IFN-γ-independent control have remained elusive. Here we show that, like IFN-γ-mediated control, IFN-γ-independent control requires the transcription factor HIF-1α. HIF-1α is activated via distinct signaling pathways and mediates divergent effects following IFN-γ-mediated and IFN-γ-independent CD4 T cell stimulation, positioning HIF-1α as a critical signaling node for control of M. tuberculosis in macrophages. Furthermore, we show that CD4 T cell production of the cytokine GM-CSF is required for IFN-γ-independent control and that GM-CSF-mediated control requires HIF-1α. These findings delineate a novel, IFN-γ-independent pathway for CD4 T cell-mediated control that begins with production of GM-CSF and leads to HIF-1α activation to restrict M. tuberculosis in infected macrophages. Advances in our understanding of CD4 T cell-mediated control of M. tuberculosis will help guide the development of new and improved vaccines for this important global pathogen.
登录
查看更多内容
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
影响因子：
5.4
作者：
Amelio, Patrizia;Portevin, Damien;Perreau, Matthieu
通讯作者：
Perreau, Matthieu
表达 CD153 的结核分枝杆菌特异性 CD4 T 细胞与人类结核病的细菌载量和疾病严重程度呈负相关。
影响因子：
8
作者：
Du Bruyn E;Ruzive S;Lindestam Arlehamn CS;Sette A;Sher A;Barber DL;Wilkinson RJ;Riou C
通讯作者：
Riou C
影响因子：
14.9
作者：
Brinkman EK;Chen T;Amendola M;van Steensel B
通讯作者：
van Steensel B
肺泡巨噬细胞从胎儿单核细胞中发展，这些单核细胞在生命的第一周通过GM-CSF分化为长寿命细胞。
DOI：
10.1084/jem.20131199
发表时间：
2013-09-23
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Guilliams M;De Kleer I;Henri S;Post S;Vanhoutte L;De Prijck S;Deswarte K;Malissen B;Hammad H;Lambrecht BN
通讯作者：
Lambrecht BN