James E. Parkinson

Many helminth parasites migrate through multiple host organs during infection, but how immune responses are relayed across these tissues is still poorly understood. To investigate the immune aspects of intertissue communication during infection, we established a percutaneous infection model with the tissue-migrating nematode Nippostrongylus brasiliensis . Profiling of the initial cutaneous immune response revealed that dermal γδ T cells become activated via an interleukin 1 receptor (IL-1R)–dependent mechanism, engage cell motility–associated transcriptional pathways, and leave the skin after parasite invasion. Inhibition of leukocyte migration prevents the accumulation of IL-17–producing γδ T cells in the lungs. Bypassing the skin phase of infection, and thereby preventing dermal γδ T cell migration, dampens early IL-17 production in the lungs. This, instead, leads to an enhanced interferon-γ (IFN-γ) response together with increased lung damage. Collectively, our data highlight a critical skin-lung axis regulating host-parasite interactions and safeguarding lung health.

The extracellular matrix (ECM) forms the scaffold in which cells reside and interact. The composition of this scaffold guides the development of local immune responses and tissue function. With the advent of multiplexed spatial imaging methodologies, investigating the intricacies of cellular spatial organisation is more accessible than ever. However, the relationship between cellular organisation and ECM composition has been broadly overlooked. Using imaging mass cytometry, we investigated the association between cellular niches and their surrounding matrix environment during allergic airway inflammation in two commonly used in-bred mouse strains. We have integrated both intracellular and extracellular analysis by first classifying cells according to their canonical marker expression and then utilising a novel pipeline to independently characterise their ECM environment. Applying this methodology across three distinct lung tissue regions we reveal region-specific and spatially constrained allergic inflammatory responses. In our model of allergic airway inflammation, recruited neutrophils were dispersed within the alveolar parenchyma, alongside a loss of alveolar type-I cells and an expansion of alveolar type-II cells. This activated parenchyma was associated with increased proximity to hyaluronan and chondroitin sulphate. In contrast, infiltrating CD11b ⁺ and MHCII ⁺ cells accumulated in the adventitial cuff specifically in BALB/c mice. This region was around the airway-adjacent pulmonary artery and aligned with an expansion of the subepithelial airway region. This expanded subepithelial region was enriched for closely interacting stromal and CD11b ⁺ immune cells which overlaid regions enriched for type-I and type-III collagen. The detailed map of cell and matrix interactions generated here provides a critical resource for understanding ECM contribution to specific lung niches during allergic disease. It reveals strain-dependent differences in inflammation and remodelling and generates novel hypotheses for targeting aspects of remodelling during allergic airway pathology.

The serous cavities are fluid-filled spaces that surround the lung, heart, and abdomen. One of their main functions is to provide protection and lubrication for their encapsulated organs. In addition to these physiological roles, the serous cavities are rich immune cell reservoirs. Although these cavity-derived immune cells have been studied ex vivo for many years, the past decade has led to substantial advances in serous cavity biology. Importantly, immune mechanisms that occur in these fluid environments and communication networks between these cavities and the tissues that they contain have been elucidated. In this Review, we aim to summarize the current knowledge of cellular and molecular interactions that govern immunology across all serous cavities, comparing animal models and human studies. A deeper understanding of how the serous cavities provide immune protection to the tissues that they encompass is likely to reveal therapeutic avenues for manipulation of these cavities to improve disease outcomes.

γδ T cells compose an evolutionarily conserved lineage of lymphocytes, with both adaptive- and innate-like characteristics, contributing to tissue homeostasis, immune surveillance, and rapid responses to stress and infection. While their functional diversity and tissue-specific roles are tightly regulated by transcriptional networks, the underlying molecular mechanisms remain incompletely understood. The transcription factor basic leucine zipper ATF-like transcription factor 3 (BATF3) plays a central role in the development of conventional type 1 dendritic cells (cDC1s). Here, we unveil BATF3 as a critical cell-intrinsic regulator of the homeostasis, functional specialization, and tissue distribution of γδ T cells. Batf3 -deficient mice display an altered composition of γδ T cell subsets, with a marked decrease in the numbers of innate-like γδ T cells across multiple organs when compared to their wild-type counterparts, independently of cDC1s. Loss of BATF3 impacts not only cell survival but also IL-17 production after γδ T cells complete their thymic development. Mechanistically, Batf3 -deficient innate-like γδ T cells exhibit transcriptional changes that disrupt pathways governing actin cytoskeleton remodelling, immunological synapse organization and cellular identity. Notably, Batf3 -deficient mice present decreased survival in a viral infection model highly dependent on innate-like γδ T cells. Together, our findings uncover a previously unrecognized BATF3-dependent pathway that controls γδ T cell morphology and function, profoundly impacting their biology.

Chitinase-like proteins (CLPs) are established biomarkers of inflammation and airway remodeling in asthma, yet their direct contribution toward disease pathogenesis is unknown. In a mouse model of type 2/type 17 airway inflammation induced by house dust mite, ragweed, and Aspergillus fumigatus (DRA) allergens, we demonstrate that murine CLPs Ym1 ( Chil3 ) and Ym2 ( Chil4 ) exert distinct and potent effects on airway extracellular matrix (ECM) composition during chronic lung pathology. Using both Ym1-knockout ( Chil3 ^−/− ) and Ym2-knockdown ( Chil4 ^KD/KD ) mice, we found that these CLPs have fundamental roles in airway remodeling that are independent of interleukin-13 (IL-13) and IL-17A signaling pathways. Antibody-mediated inhibition of CLPs after pathology has developed reverses airway remodeling independently of chronic inflammation. However, this inhibition is not sufficient to reduce airway hyperresponsiveness (AHR) in allergic animals. Instead, the absence of CLPs increases epithelial damage and leads to a loss of bronchial epithelial integrity. This work disentangles chronic IL-13 and IL-17A signaling from the development of allergic airway pathology and reveals CLPs as orchestrators of airway remodeling that can produce both protective and adverse outcomes.

Spatial proteomics technologies now profile cells and the extracellular matrix (ECM) together in situ . Yet analysis tools remain cell-centric, despite the ECM playing an essential role in health and disease. Here we present Mantpy, a frame-work that represents the ECM, and its interface with cells, as spatial graphs. Mantpy builds ECM graphs directly from matrix markers and links them with cell graphs for joint cell–ECM analysis, supporting graph statistics, explainable graph deep learning and visualisation. Mantpy extends from a single ECM marker to multiplexed cell–ECM panels. It recovers layered tissue architecture in the intestine from collagen IV alone, quantifies infection-associated ECM remodelling in mouse liver, and relates cells to the surrounding matrix in mouse lung, where cellular context recovers synthetically corrupted matrix labels. Released with ECM-inclusive datasets and interoperating with the scverse ecosystem and pytorch geometric. Mantpy brings the matrix into spatial analysis alongside the cell.

Chitinase-like proteins (CLPs) are of wide interest due to their significant roles during both biological and pathological processes. Human CLPs such as YKL-40 have been suggested as biomarkers of disease severity in many conditions. Murine CLPs include Brp39, Ym1, and Ym2 and these are similarly upregulated in multiple mouse models of pathology. Investigation of these molecules, particularly Ym1 and Ym2, is plagued by complexity in the genomic locus due to recent gene duplication events in the C57BL/6 strain. Using a novel CRISPR-Cas9 targeting approach involving CB6 mixed background embryos, we generated a Ym1 deficient mouse. Validation using flow cytometry, ELISA, and immunofluorescence confirmed no expression of mature Ym1 protein with no alteration in the expression of related chitinases/CLP genes including Chia and Chil4. This new transgenic mouse line will be key for investigating CLP functions and the genetic approach utilised may provide a useful strategy for other genes which show differences between inbred mouse strains.

Many helminth parasites migrate through multiple host organs during infection but how immune responses are relayed across these tissues is still poorly understood. To investigate the cellular and molecular aspects of inter-tissue communication during infection we established a percutaneous infection model with the tissue-migrating nematode Nippostrongylus brasiliensis . High-dimension profiling of the initial cutaneous immune response revealed that dermal γδ T cells become activated via an IL-1R-dependent mechanism, engage cell motility-associated transcriptional pathways and leave the skin after parasite invasion. Chemical and genetic inhibition of leukocyte migration prevents the accumulation of IL-17-producing γδ T cells in the lungs. Notably, bypassing the skin phase of infection, and therefore preventing dermal γδ T cell migration, dampens the increase in early IL-17 production in the lungs, and, instead, leads to enhanced IFN-γ responses together with increased lung damage. Collectively, our data highlights a critical skin–lung axis regulating host-parasite interactions and safeguarding lung health.

The extracellular matrix (ECM) forms the scaffold in which cells reside and interact. The composition of this scaffold guides the development of local immune responses and tissue function. With the advent of multiplexed spatial imaging methodologies, investigating the intricacies of cellular spatial organisation are more accessible than ever. However, the relationship between cellular organisation and ECM composition has been broadly overlooked. Using imaging mass cytometry, we investigated the association between cellular niches and their surrounding matrix environment during allergic airway inflammation in two commonly used mouse strains. By first classifying cells according to their canonical intracellular markers and then by developing a novel analysis pipeline to independently characterise a cells ECM environment, we integrated analysis of both intracellular and extracellular data. Applying this methodology to three distinct tissue regions we reveal disparate and restricted responses. Recruited neutrophils were dispersed within the alveolar parenchyma, alongside a loss of alveolar type I cells and an expansion of alveolar type II cells. This activated parenchyma was associated with increased proximity to hyaluronan and chondroitin sulphate. In contrast, infiltrating CD11b ⁺ and MHCII ⁺ cells accumulated in the adventitial cuff and aligned with an expansion of the subepithelial layer. This expanded subepithelial region was enriched for closely interacting stromal and CD11b ⁺ immune cells which overlaid regions enriched for type-I and type-III collagen. The cell-cell and cell-matrix interactions identified here will provide a greater understanding of the mechanisms and regulation of allergic disease progression across different inbred mouse strains and provide specific pathways to target aspects of remodelling during allergic pathology. Graphical