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. In their Review, Becher et al. discuss how selected cytokine networks preserve, destabilize and restore central nervous system integrity.
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. Here the authors show that SERPINA3 is a soluble SIRPα ligand with immunosuppressive and therapeutic activity against inflammatory and autoimmune diseases, whereas cancer cells overexpress SERPINA3 and blocking it can be protective.
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. Khatri and colleagues assembled a single-cell atlas of 1 million human neutrophils based on the integration of 43 independent single-cell transcriptome datasets to define multiple neutrophil subsets with distinct functions across tissues and disease states.
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. Ballesteros-Tato and colleagues identify a spatially restricted follicular helper T cell-dependent interleukin-2 niche critical for regulatory T cell stability in gut-associated lymphoid tissues.
Regulatory T (Treg) cells maintain immunological tolerance, but the cellular niches sustaining them across tissues are poorly defined. Work now identifies T follicular helper cells as a source of IL-2 that supports Treg cells in gut-associated lymphoid tissue and promotes intestinal immune homeostasis.
