McMaster Immunology Research Centre, M. G. DeGroote Institute for Infectious Disease Research, & Department of Pathology & Molecular Medicine, McMaster University, Hamilton, ON, L8S 4K1, Canada.
Department of Biochemistry and Biomedical Sciences & Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, L8N 3Z5, Canada.
Cell. 2018 Nov 29;175(6):1634-1650.e17. doi: 10.1016/j.cell.2018.09.042. Epub 2018 Oct 25.
Innate immune memory is an emerging area of research. However, innate immune memory at major mucosal sites remains poorly understood. Here, we show that respiratory viral infection induces long-lasting memory alveolar macrophages (AMs). Memory AMs are programed to express high MHC II, a defense-ready gene signature, and increased glycolytic metabolism, and produce, upon re-stimulation, neutrophil chemokines. Using a multitude of approaches, we reveal that the priming, but not maintenance, of memory AMs requires the help from effector CD8 T cells. T cells jump-start this process via IFN-γ production. We further find that formation and maintenance of memory AMs are independent of monocytes or bone marrow progenitors. Finally, we demonstrate that memory AMs are poised for robust trained immunity against bacterial infection in the lung via rapid induction of chemokines and neutrophilia. Our study thus establishes a new paradigm of immunological memory formation whereby adaptive T-lymphocytes render innate memory of mucosal-associated macrophages.
先天免疫记忆是一个新兴的研究领域。然而，主要黏膜部位的先天免疫记忆仍然知之甚少。在这里，我们表明呼吸道病毒感染会诱导持久的记忆肺泡巨噬细胞（AMs）。记忆 AM 被编程表达高水平的 MHC II、防御准备基因特征和增加的糖酵解代谢，并在再刺激时产生中性粒细胞趋化因子。通过多种方法，我们揭示了记忆 AM 的启动（而不是维持）需要效应性 CD8 T 细胞的帮助。T 细胞通过产生 IFN-γ 来启动这个过程。我们还发现，记忆 AM 的形成和维持与单核细胞或骨髓祖细胞无关。最后，我们证明记忆 AM 通过快速诱导趋化因子和嗜中性粒细胞，为肺部的细菌感染做好了强大的训练性免疫的准备。因此，我们的研究建立了一个新的免疫记忆形成范式，即适应性 T 淋巴细胞使黏膜相关巨噬细胞具有先天记忆。
