Antibody affinity maturation can favor a few high-affinity clones. Spatially isolated germinal centers limit clonal dominance and preserve antibody response breadth.
Host resistance to infection is initially determined by how well primed the innate immune system is to respond on first exposure to an invader, yet the mechanisms underlying this priming remain incompletely understood. Here we found that basal autophagy suppressed the expression of Il1a in alveolar macrophages (AMs) and an otherwise protective innate immune priming against Staphylococcus aureus and influenza A virus (IAV), independently of the microbiome and adaptive immunity. Inactivating autophagy genes in AMs led to elevated expression of IL-1α in AMs, which subsequently enhanced IL-1R-MyD88 signaling in neutrophils and increased the recruitment of myeloid cells to the lung. As a result, autophagy-deficient mice showed more efficient clearance of S. aureus along with reduced lung damage and inflammation. Similar to genetic inactivation of autophagy, overexpression of IL-1α in AMs conferred broad spectrum protection against S. aureus and IAV, suggesting a possible strategy to fine-tune immune responses to combat important respiratory infections. Wang and colleagues show that autophagy deficiency in alveolar macrophages upregulates the expression of IL-1α and increases resistance to respiratory infections.
Embryonic hematopoiesis is thought to occur exclusively in the extraembryonic yolk sac before hematopoietic stem cells (HSCs) arise in the aorta–gonad–mesonephros region. Here we identify a previously unrecognized hematopoietic site at the maternal–fetal interface in mice, termed MIXER (Maternally Interfaced eXtraEmbRyonic) tissue, which develops contemporaneously with the yolk sac and exhibits robust hematopoietic activity. MIXER contains abundant hematopoietic precursors, including classical CSF1R+ erythro-myeloid progenitors and a unique embryonic CD4+CSF1R− Erythro-Myeloid PRogenitOR (eEMPROR) population. Lineage-tracing experiments demonstrate that eEMPROR cells contribute to select macrophage subpopulations during fetal development, primarily in the perivascular space. Notably, early human placental villi, before HSC emergence, also harbor CD4+ nucleated erythrocytes, indicating a conserved hematopoietic role for the maternal–fetal interface. These findings establish MIXER as an anatomically distinct niche for embryonic hematopoiesis and expand the developmental map of blood cell emergence in mammals. Jain et al. identify a unique extraembryonic hematopoietic niche at the maternal–fetal interface that is distinct from the yolk sac and is capable of producing CD4+CSF1R− erythro-myeloid progenitors.
