Marco De Giovanni

Elderly individuals affected by COVID-19 are vulnerable to severe respiratory failure for reasons that have remained poorly defined. Here, we show that platelet-released serotonin drives lung pathology in a mouse model of age-associated disease severity after SARS-CoV-2 infection. In middle-aged mice and aged human healthy donors, platelet serotonin release upon activation was enhanced, and increased morbidity with respiratory dysfunction was associated with activated platelets aggregating and promoting fibrin deposition in the lung microvasculature. Pharmacologic or genetic disruption of serotonin uptake, or blockade of serotonin-dependent signaling, attenuated platelet activation and protected against respiratory distress, independently of viral replication and immune responses. Inhibition of fibrin formation similarly reduced disease severity, implicating serotonin-driven platelet procoagulant activity as a key contributor to age-related lung dysfunction. Thus, serotonin-mediated platelet procoagulant activity is a major contributor to respiratory insufficiency during SARS-CoV-2 infection and a potential therapeutic target for preserving pulmonary function, particularly in the elderly.

The immune system is deeply shaped by its anatomical context, with spatial organization emerging as a fundamental principle of immune regulation. Recent advances in spatial omics technologies—encompassing transcriptomics, proteomics, metabolomics, lipidomics, and phosphoproteomics—have revolutionized our ability to study immune processes within intact tissue environments. By preserving spatial coordinates while capturing high‐dimensional molecular data, these technologies offer unprecedented insight into how immune cell states and functions are governed by local cues and tissue architecture. In this review, we provide an overview of the major spatial omics platforms, emphasizing methodologies that have gained traction within the immunology community and in our own research. We then illustrate how these tools have begun to elucidate the logic of immune compartmentalization across anatomically complex tissues. While not exhaustive, we highlight selected examples from the intestine, secondary lymphoid organs, and liver to show how spatial omics has uncovered region‐specific immune programs, microenvironmental niches, and context‐dependent signaling pathways. Together, these studies demonstrate how spatial omics technologies are redefining immunological inquiry—shifting the focus from isolated cell types to their spatially embedded roles in tissue physiology and pathology.

Chronic hepatitis B virus (HBV) infection is marked by dysfunctional HBV-specific CD8⁺ T cells, and restoring their effector activity is a major therapeutic goal. Here, we generated HBV-specific CD4⁺ T cell receptor transgenic mice to show that CD4⁺ effector T cells can prevent and reverse the CD8⁺ T cell dysfunction induced by hepatocellular priming. This rescue enhances antiviral CD8⁺ T cell function and suppresses viral replication. CD4⁺ T cell help occurs directly within the liver, independent of secondary lymphoid organs, and requires local antigen recognition. Kupffer cells, rather than dendritic cells, are the critical antigen-presenting platform. CD4⁺ T cells license Kupffer cells via CD40–CD40L interactions, triggering interleukin (IL)-12 and IL-27 production. IL-12 expands the CD4⁺ T cell pool, while IL-27 is essential for CD8⁺ T cell rescue. Exogenous IL-27 similarly restores HBV-specific CD8⁺ T cell function in mice and in T cells isolated from chronically infected patients. These findings identify IL-27 as a tractable immunotherapeutic target in chronic HBV infection.

The adaptation of immune cells to their local microenvironments in our body is central to tissue homeostasis and linked to disease. In this commentary, we envision how future therapeutics could leverage local immunity to selectively target specific niches for disease treatment.

G protein‐coupled receptors (GPCRs) are vital cell surface receptors that govern a myriad of physiological functions. Despite their crucial role in regulating antitumor immunity and tumorigenesis, therapeutic applications targeting GPCRs in oncology are currently limited. This review offers a focused examination of selected protumorigenic chemokine and metabolite‐sensing GPCRs. Specifically, the review highlights five GPCRs able to orchestrate tumor immunobiology at three main levels: tumor immunity, cancer cell expansion, and blood vessel development. The review culminates by illuminating emerging therapies and discussing innovative strategies to harness the full potential of GPCR‐targeted treatments, by applying a multireceptor and patient‐specific logic.

The blood-brain barrier (BBB) acquires unique properties to regulate neuronal function during development. The formation of the BBB, which occurs in tandem with angiogenesis, is directed by the Wnt/β-catenin signaling pathway. Yet the exact molecular interplay remains elusive. Our study reveals the G protein–coupled receptor GPR126 as a critical target of canonical Wnt signaling, essential for the development of the BBB’s distinctive vascular characteristics and its functional integrity. Endothelial cell–specific deletion of the Gpr126 gene in mice induced aberrant vascular morphogenesis, resulting in disrupted BBB organization. Simultaneously, heightened transcytosis in vitro compromised barrier integrity, resulting in enhanced vascular permeability. Mechanistically, GPR126 enhanced endothelial cell migration, pivotal for angiogenesis, acting through an interaction between LRP1 and β ₁ integrin, thereby balancing the levels of β ₁ integrin activation and recycling. Overall, we identified GPR126 as a specifier of an organotypic vascular structure, which sustained angiogenesis and guaranteed the acquisition of the BBB properties during development.

Peyer’s patches (PPs) are lymphoid structures situated adjacent to the intestinal epithelium that support B cell responses that give rise to many intestinal IgA-secreting cells. Induction of isotype switching to IgA in PPs requires interactions between B cells and TGFβ-activating conventional dendritic cells type 2 (cDC2s) in the subepithelial dome (SED). However, the mechanisms promoting cDC2 positioning in the SED are unclear. Here, we found that PP cDC2s express GPR35, a receptor that promotes cell migration in response to various metabolites, including 5-hydroxyindoleacetic acid (5-HIAA). In mice lacking GPR35, fewer cDC2s were found in the SED, and frequencies of IgA ⁺ germinal center (GC) B cells were reduced. IgA plasma cells were reduced in both the PPs and lamina propria. These phenotypes were also observed in chimeric mice that lacked GPR35 selectively in cDCs. GPR35 deficiency led to reduced coating of commensal bacteria with IgA and reduced IgA responses to cholera toxin. Mast cells were present in the SED, and mast cell–deficient mice had reduced PP cDC2s and IgA ⁺ cells. Ablation of tryptophan hydroxylase 1 (Tph1) in mast cells to prevent their production of 5-HIAA similarly led to reduced PP cDC2s and IgA responses. Thus, mast cell–guided positioning of GPR35 ⁺ cDC2s in the PP SED supports induction of intestinal IgA responses.

In this manuscript, the authors delve deep into the heterogeneity of macrophages, which play pivotal roles in development and disease. Despite the significance of macrophages, there's a noted gap in the understanding of their diversity, function, and specification during human development. The following bullet points highlight the strengths and important findings of this work. Comprehensive scRNA-seq Map: To address the knowledge gap, a scRNA-seq map was crafted, adeptly capturing the dynamics of human macrophage specification. This map spans from PCW 4-26 and impressively covers 19 distinct tissues. Discovery of distinct macrophage populations: Among the 15 identified macrophage subtypes, two significant populations were identified: a) A microglia-like population bearing molecular and morphological resemblances to central nervous system (CNS) microglia. b) A proangiogenic population. Unexpected locations of microglia-like cells: These cells, reminiscent of CNS microglia, were detected in unexpected sites, including the fetal epidermis, testicle, and heart. Notably, in the early epidermis, they established themselves as the primary immune population. Polarized distribution & interaction: The microglia-like cells showcased a distinct polarized distribution along the dorsal-lateral-ventral axis. Their interactions with neural crest cells were of particular note, as they influenced the differentiation of these cells along the melanocyte lineage. Insight into the positioning of proangiogenic macrophages: Through rigorous spatial and differentiation trajectory analyses, the authors discerned the positioning of proangiogenic macrophages. These cells predominantly align perivascularly across fetal organs. Intriguingly, there are suggestions that these macrophages might originate from the yolk sac, much like microglia. In summary, this manuscript stands out as a significant contribution to the field, offering a detailed and expansive view of human macrophage heterogeneity and illuminating their diverse roles throughout the stages of development.