Becker Samuel H, Ronayne Christine E, Bold Tyler D, Jenkins Marc K
Center for Immunology, Department of Microbiology and Immunology, University of Minnesota Twin Cities School of Medicine, Minneapolis, Minnesota, United States of America.
Division of Infectious Diseases & International Medicine, Department of Medicine, University of Minnesota Twin Cities School of Medicine, Minneapolis, Minnesota, United States of America.
PLoS Pathog. 2025 Jun 9;21(6):e1013208. doi: 10.1371/journal.ppat.1013208. eCollection 2025 Jun.
Although lung myeloid cells provide an intracellular niche for Mycobacterium tuberculosis (Mtb), CD4+ T cells limit Mtb growth in these cells to protect the host. The CD4+ T cell activities including interferon-γ (IFN-γ) production that account for this protection are poorly understood. Using intravenous antibody labeling and lineage-tracing reporter mice, we show that monocyte-derived macrophages (MDMs), rather than phenotypically similar monocytes or dendritic cells, are preferentially infected with Mtb in murine lungs. MDMs were recruited to the lungs by Mtb-specific CD4+ T cells via IFN-γ, which promoted the extravasation of monocyte precursors from the blood. It was possible that CD4+ T cells recruited infectable MDMs because these cells are uniquely poised to receive cognate MHCII-mediated help to control intracellular bacteria. Mice with MHCII deficiency in monocyte-derived cells had normal Mtb-specific CD4+ T cell activation, expansion and differentiation but the CD4+ T cells were unable to attenuate Mtb growth. Using single cell RNA sequencing, we showed that MDMs receiving cognate MHCII-mediated help from CD4+ T cells upregulated glycolytic genes associated with Mtb control. Overall, the results indicate that CD4+ T cells recruit infectable MDMs to the lungs and then trigger glycolysis-dependent bacterial control in the MDMs by engaging their MHCII-bound Mtb peptides. Moreover, the results suggest that cognate MHCII-mediated help to promote MDM glycolysis is an essential, IFN-γ-independent effector function of Mtb-specific CD4+ T cells.
虽然肺髓样细胞为结核分枝杆菌（Mtb）提供了一个细胞内微环境，但CD4+ T细胞限制了Mtb在这些细胞中的生长，以保护宿主。人们对包括产生γ干扰素（IFN-γ）在内的、促成这种保护作用的CD4+ T细胞活性了解甚少。利用静脉内抗体标记和谱系追踪报告小鼠，我们发现，在小鼠肺部，源自单核细胞的巨噬细胞（MDM），而非表型相似的单核细胞或树突状细胞，更易被Mtb感染。Mtb特异性CD4+ T细胞通过IFN-γ将MDM招募至肺部，IFN-γ促进单核细胞前体从血液中渗出。CD4+ T细胞招募可被感染的MDM是有可能的，因为这些细胞独特地准备好接受同源MHCII介导的帮助以控制细胞内细菌。单核细胞衍生细胞中存在MHCII缺陷的小鼠，其Mtb特异性CD4+ T细胞的激活、扩增和分化正常，但CD4+ T细胞无法减弱Mtb的生长。利用单细胞RNA测序，我们发现，从CD4+ T细胞接受同源MHCII介导帮助的MDM上调了与Mtb控制相关的糖酵解基因。总体而言，结果表明，CD4+ T细胞将可被感染的MDM招募至肺部，然后通过与它们MHCII结合的Mtb肽段相互作用，触发MDM中依赖糖酵解的细菌控制。此外，结果表明，同源MHCII介导的促进MDM糖酵解的帮助是Mtb特异性CD4+ T细胞的一种必不可少的、不依赖IFN-γ的效应器功能。
