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.

Tissue-resident macrophages originate from distinct developmental sources, but their adult replenishment is thought to depend exclusively on circulating monocytes. Here we identify a previously unrecognized CD4-lineage erythro-myeloid progenitor (EMPROR) in the adult bone marrow that provides an alternative pathway for macrophage generation. EMPROR cells are phenotypically and transcriptionally distinct from hematopoietic stem cells, common myeloid progenitors and monocyte precursors, lacking Csf1r and Ccr2 while expressing Cd4 and Kit. Single-cell RNA sequencing, RNA velocity analysis and lineage assays reveal macrophage, neutrophil, megakaryocytic and erythroid potential. EMPROR cells generate perivascular and tumor-associated macrophages independently of CCR2-mediated monocyte recruitment and contribute to erythroid and granulocytic lineages under inflammatory and neoplastic conditions. Transcriptomic comparisons position EMPROR cells closest to embryonic erythro-myeloid progenitors, indicating the persistence of an embryonic-like program in adult bone marrow. These findings reveal an alternative pathway of adult myelopoiesis that sustains macrophage diversity beyond the classical monocyte lineage.

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.

Cytokines are critical regulators of central nervous system (CNS) integrity, acting not only as immune messengers but also as signals that coordinate interactions among glial and neuronal cells, resident macrophages, such as microglia and border-associated macrophages, and infiltrating leukocytes. These circuits establish basal immune tone, shape responses to perturbation, and promote tissue adaptation and recovery. In this Review, we examine selected cytokine pathways across homeostasis, inflammatory or degenerative tissue damage and repair to develop a framework for how cytokine networks preserve, destabilize and restore CNS integrity. We focus on CSF-1, IL-34, TGFβ and IL-33 in homeostasis; IL-1, TNF, GM-CSF and IFNγ in inflammation; type I and II interferons in antiviral and neurodegenerative states; and IL-12 at the interface of innate sensing, adaptive immunity and tissue-protective adaptation. By focusing on instructive modules, we highlight broader organizing principles and how cytokine miscalibration can lead to neurological disease across diverse contexts.

SIRPα is an inhibitory receptor with the canonical ligand CD47. Here, we show that human serine protease inhibitor A3 (SERPINA3) and its mouse ortholog SERPINA3k function as soluble binders and activators of SIRPα, suppressing SIRPα[+] macrophages, neutrophils, dendritic cells and natural killer cells. SERPINA3(k) treatment alleviates lipopolysaccharide-induced pneumonia and ameliorates experimental autoimmune encephalomyelitis and rheumatoid arthritis. Although wild-type SERPINA3 provokes inflammation in cardiomyocytes and brain vascular endothelial cells, the SERPINA3D2 mutant, identified through functional domain mapping for SIRPα interaction, abolishes these adverse effects while retaining full inhibitory capacity. Notably, cancer cells secrete large amounts of SERPINA3(k), exceeding CD47 levels. Anti-SERPINA3(k) antibodies, used alone or in combination with blockade of programmed cell death 1 receptor/programmed cell death ligand 1, inhibit tumor growth in multiple preclinical models. This work identifies a potent soluble SIRPα ligand, offering effective therapeutic strategies for inflammatory/autoimmune diseases and a promising target for cancer immunotherapy.

Neutrophils, the most abundant leukocytes in human blood, have multifaceted roles in health and disease. Here we assembled a single-cell atlas of human neutrophils (SCAHN) by integrating transcriptome data from 1 million human neutrophils from 781 samples and 43 independent datasets. Using SCAHN, we identified multiple neutrophil subsets with distinct functions across tissues and robust changes in gene expression and subset proportions in infection, cancer, immune suppression and sex differences at single-cell resolution. Cross-species reference mapping of mouse and nonhuman primate neutrophils onto SCAHN revealed both conserved and species-specific features. Using 17,023 bulk blood transcriptome profiles from 40 datasets, we found that neutrophil-specific signatures predicted mortality in acutely ill patients at presentation, were associated with cancer diagnosis and survival, and correlated with metabolic dysfunction and long-term all-cause mortality. Our study highlights how neutrophil biology can improve immune risk stratification and develop effective diagnostic and therapeutic strategies.

Germinal centers (GCs) form as confined clusters of motile cells within individual lymphoid follicles. The role of confinement in GC B cell evolutionary events is unknown. Here, using mice with reduced GC confinement because of deficiency in Gα13-dependent G-protein-coupled receptor signaling, we observed GC-GC trafficking in confinement-defective lymph nodes (LNs). In multicolor clonal lineage tracing mice, de-confined GCs minimally diversified their color palettes with respect to one another. Spatial B cell receptor sequencing revealed greater clonal crossover between neighboring GCs in the setting of dispersal. The total GC B cell repertoire of LNs with inter-GC exchange also decreased in overall diversity because of increased skewing toward top clones. As an outcome, LNs with de-confined GCs more strongly favored clones responding to accessible epitopes while losing clones binding to other portions of antigen. Together, our findings suggest that confinement supports antibody breadth by moderating the spread of dominant clones and preserving unique trajectories in individual GC responses.

Follicular helper T (TFH) cells are well known for their role in supporting B cell responses. Here, we identify a critical B cell-independent function for TFH cells in sustaining regulatory T (Treg) cells within gut-associated lymphoid tissues (GALT). We demonstrate that TFH cells produce interleukin-2 (IL-2) at the T cell-B cell border and within interfollicular regions and that this localized IL-2 is required to maintain GALT Treg cell homeostasis and restrain the expansion of pathogenic effector T cells. Mice selectively lacking IL-2-producing TFH cells develop colitis and fatal multiorgan inflammation, driven by impaired GALT Treg cell responses and uncontrolled effector T cell activation. Broad-spectrum antibiotic treatment alleviates both intestinal and extraintestinal pathology, indicating that loss of tolerance to commensal-derived antigens is a key driver of disease. Together, these findings define a spatially restricted TFH cell-derived IL-2 niche critical for GALT Treg cell stability and uncover an unexpected immunoregulatory role for TFH cells in maintaining gastrointestinal tolerance beyond B cell help.