Optimal generation of hepatic tissue-resident memory CD4 T cells requires IL-1 and IL-2.
Optimal generation of hepatic tissue-resident memory CD4 T cells requires IL-1 and IL-2.
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DOI：
10.1073/pnas.2214699120
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发表时间：
2023-04-18
影响因子：
11.1
通讯作者：
McSorley, Stephen J.
中科院分区：
文献类型：
--
作者：
Depew, Claire E.;Rixon, Jordan A.;McSorley, Stephen J.
系统性沙门氏菌每年导致约 371,500 人死亡，主要影响年轻人或免疫功能低下的个体，因此需要一种有效的亚单位疫苗。完全防御沙门氏菌需要 CD4 (TRM) 组织驻留记忆 T 细胞，但亚单位疫苗通常诱导循环记忆细胞而不是组织驻留细胞群。这项研究表明，肝脏炎症增加了肝脏 CD4 TRM 的形成，并增强了 SseB 亚单位疫苗接种提供的保护。肝脏 CD4 TRM 的最佳形成需要细胞因子 IL-1 和 IL-2。这为了解针对重要人类病原体的保护性记忆 T 细胞的形成提供了机制见解。肝脏 CD4 组织驻留记忆 T 细胞 (TRM) 是抵御沙门氏菌感染的有力保护所必需的；然而，人们对这种 T 细胞群的产生知之甚少。为了探究炎症的影响，我们开发了一种简单的沙门氏菌特异性 T 细胞转移系统，可以直接可视化肝脏 TRM 的形成。沙门氏菌特异性 (SM1) T 细胞受体 (TCR) 转基因 CD4 T 细胞在体外被激活，并过继转移至 C57BL/6 小鼠体内，同时过量服用对乙酰氨基酚或单核细胞增生李斯特菌感染可诱导肝脏炎症。在这两个模型系统中，局部组织反应加剧了肝脏 CD4 TRM 的形成。肝脏炎症还增强了亚单位沙门氏菌疫苗提供的次优保护，该疫苗通常会诱导循环记忆 CD4 T 细胞。为了进一步阐明 CD4 TRM 形成响应肝脏炎症的机制，通过 RNAseq、骨髓嵌合体和体内中和检查了各种细胞因子。令人惊讶的是，发现IL-2和IL-1可以增强CD4 TRM的形成。因此，局部炎症介质可增强 CD4 TRM 群体，并可增强次优疫苗提供的保护性免疫力。这些知识将为开发更有效的侵袭性非伤寒沙门氏菌病（iNTS）疫苗奠定基础。
Systemic Salmonella causes about 371,500 deaths a year, predominantly impacting young or immunocompromised individuals, and an effective subunit vaccine is needed. CD4 (TRM) tissue-resident memory T cells are required for complete protection against Salmonella, but subunit vaccines typically induce circulating memory cells rather than tissue-resident populations. This study demonstrates that liver inflammation increased the formation of hepatic CD4 TRM and enhanced protection provided by SseB subunit vaccination. Cytokines IL-1 and IL-2 were required for optimal formation of hepatic CD4 TRM. This provides mechanistic insight into the formation of protective memory T cells against an important human pathogen. Hepatic CD4 tissue-resident memory T cells (TRM) are required for robust protection against Salmonella infection; however, the generation of this T cell population is poorly understood. To interrogate the contribution of inflammation, we developed a simple Salmonella-specific T cell transfer system that allowed direct visualization of hepatic TRM formation. Salmonella-specific (SM1) T cell receptor (TCR) transgenic CD4 T cells were activated in vitro and adoptively transferred into C57BL/6 mice while hepatic inflammation was induced by acetaminophen overdose or L. monocytogenes infection. In both model systems, hepatic CD4 TRM formation was accentuated by local tissue responses. Liver inflammation also enhanced the suboptimal protection provided by a subunit Salmonella vaccine which typically induces circulating memory CD4 T cells. To further elucidate the mechanism of CD4 TRM formation in response to liver inflammation, various cytokines were examined by RNAseq, bone marrow chimeras, and in vivo neutralization. Surprisingly, IL-2 and IL-1 were found to enhance CD4 TRM formation. Thus, local inflammatory mediators enhance CD4 TRM populations and can boost the protective immunity provided by a suboptimal vaccine. This knowledge will be foundational for the development of a more effective vaccine against invasive nontyphoidal salmonellosis (iNTS).
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DOI：
10.1084/jem.20142101
发表时间：
2015-08-24
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Glennie ND;Yeramilli VA;Beiting DP;Volk SW;Weaver CT;Scott P
通讯作者：
Scott P
影响因子：
3.1
作者：
McSorley, SJ;Jenkins, MK
通讯作者：
Jenkins, MK
影响因子：
32.4
作者：
McSorley, SJ;Asch, S;Jenkins, MK
通讯作者：
Jenkins, MK
影响因子：
30.5
作者：
Huang, Li-Rung;Wohlleber, Dirk;Knolle, Percy A.
通讯作者：
Knolle, Percy A.
影响因子：
4.4
作者：
Lee, Seung-Joo;Benoun, Joseph;McSorley, Stephen J.
通讯作者：
McSorley, Stephen J.