Department of Anatomy, Physiology, and Cell Biology, School of Veterinary Medicine, University of California, Davis, CA 95616.
Proc Natl Acad Sci U S A. 2023 Apr 18;120(16):e2214699120. doi: 10.1073/pnas.2214699120. Epub 2023 Apr 11.
Hepatic CD4 tissue-resident memory T cells (TRM) are required for robust protection against infection; however, the generation of this T cell population is poorly understood. To interrogate the contribution of inflammation, we developed a simple -specific T cell transfer system that allowed direct visualization of hepatic TRM formation. -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 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 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).
肝组织驻留记忆 T 细胞（TRM）是抵抗感染的强大保护所必需的；然而，这种 T 细胞群体的产生还知之甚少。为了探究炎症的贡献，我们开发了一种简单的特异性 T 细胞转移系统，该系统允许直接观察肝 TRM 的形成。特异性（SM1）T 细胞受体（TCR）转基因 CD4 T 细胞在体外激活，并在肝内炎症由对乙酰氨基酚过量或感染诱导时被过继转移到 C57BL/6 小鼠中。在这两种模型系统中，肝 CD4 TRM 的形成都被局部组织反应所增强。肝炎症还增强了亚最佳保护的亚单位疫苗，该疫苗通常诱导循环记忆 CD4 T 细胞。为了进一步阐明肝炎症对 CD4 TRM 形成的机制，通过 RNAseq、骨髓嵌合体和体内中和研究了各种细胞因子。令人惊讶的是，IL-2 和 IL-1 被发现增强了 CD4 TRM 的形成。因此，局部炎症介质增强了 CD4 TRM 群体，并可以增强亚最佳疫苗提供的保护性免疫。这些知识将为开发针对侵袭性非伤寒沙门氏菌病（iNTS）的更有效的疫苗奠定基础。
