The members of the Mycobacterium tuberculosis complex (MTBC) causing human tuberculosis comprise 10 phylogenetic lineages that differ in their geographical distribution. The human consequences of this phylogenetic diversity remain poorly understood. Here, we assessed the phenotypic properties at the host-pathogen interface of 14 clinical strains representing five major MTBC lineages. Using a human in vitro granuloma model combined with bacterial load assessment, microscopy, flow cytometry, and multiplexed-bead arrays, we observed considerable intra-lineage diversity. Yet, modern lineages were overall associated with increased growth rate and more pronounced granulomatous responses. MTBC lineages exhibited distinct propensities to accumulate triglyceride lipid droplets—a phenotype associated with dormancy—that was particularly pronounced in lineage 2 and reduced in lineage 3 strains. The most favorable granuloma responses were associated with strong CD4 and CD8 T cell activation as well as inflammatory responses mediated by CXCL9, granzyme B, and TNF. Both of which showed consistent negative correlation with bacterial proliferation across genetically distant MTBC strains of different lineages. Taken together, our data indicate that different virulence strategies and protective immune traits associate with MTBC genetic diversity at lineage and strain level.

Preeclampsia (PE), a major cause of maternal and perinatal mortality with highly heterogeneous causes and symptoms, is usually complicated by gestational diabetes mellitus (GDM). However, a comprehensive understanding of the immune microenvironment in the placenta of PE and the differences between PE and GDM is still lacking. In this study, cytometry by time of flight indicated that the frequencies of memory-like Th17 cells (CD45RA⁻CCR7⁺IL-17A⁺CD4⁺), memory-like CD8⁺ T cells (CD38⁺CXCR3⁻CCR7⁺Helios⁻CD127⁻CD8⁺) and pro-inflam Macs (CD206⁻CD163⁻CD38^midCD107a^lowCD86^midHLA-DR^midCD14⁺) were increased, while the frequencies of anti-inflam Macs (CD206⁺CD163⁻CD86^midCD33⁺HLA-DR⁺CD14⁺) and granulocyte myeloid-derived suppressor cells (gMDSCs, CD11b⁺CD15^hiHLA-DR^low) were decreased in the placenta of PE compared with that of normal pregnancy (NP), but not in that of GDM or GDM&PE. The pro-inflam Macs were positively correlated with memory-like Th17 cells and memory-like CD8⁺ T cells but negatively correlated with gMDSCs. Single-cell RNA sequencing revealed that transferring the F4/80⁺CD206⁻ pro-inflam Macs with a Folr2⁺Ccl7⁺Ccl8⁺C1qa⁺C1qb⁺C1qc⁺ phenotype from the uterus of PE mice to normal pregnant mice induced the production of memory-like IL-17a⁺Rora⁺Il1r1⁺TNF⁺Cxcr6⁺S100a4⁺CD44⁺ Th17 cells via IGF1–IGF1R, which contributed to the development and recurrence of PE. Pro-inflam Macs also induced the production of memory-like CD8⁺ T cells but inhibited the production of Ly6g⁺S100a8⁺S100a9⁺Retnlg⁺Wfdc21⁺ gMDSCs at the maternal–fetal interface, leading to PE-like symptoms in mice. In conclusion, this study revealed the PE-specific immune cell network, which was regulated by pro-inflam Macs, providing new ideas about the pathogenesis of PE.