Biology subjects

Shaw, T. N.

Publications and source records attributed to Shaw, T. N..

5 recordsLinked to original sources

bioRxiv2025

Comprehensive analysis of myeloid reporter mice

Macrophages are a pivotal cell type within the synovial lining and sub-lining of the joint, playing a crucial role in maintaining homeostasis of synovium. Although fate-mapping techniques have been employed to differentiate synovial macrophages from other synovial myeloid cells, no comprehensive study has yet been conducted within the mouse synovial macrophage compartment. In this study, we present, for the first time, lineage tracing results from 18 myeloid-specific fate-mapping models in mouse peripheral blood (PB) and synovial tissue. The identification of synovial macrophages and monocyte-lineage cells through flow cytometry was further validated using cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) datasets. These findings provide a valuable methodological tool for researchers to select appropriate models for studying the function of synovial myeloid cells and serve as a reference for investigations in other tissue types.

immunology↗

bioRxiv2023

Postnatal intestinal epithelial maturation by LSD1 controls the small intestinal immune cell composition independently from the microbiota

Postnatal development of the gastrointestinal tract involves the establishment of the commensal microbiota, maturation of the intestinal epithelium, and the acquisition of immune tolerance via a balanced immune cell composition. While studies have uncovered an interplay between the commensal microbiota and immune system development, less is known about the role of the maturing epithelium. Here, we comprehensively show that intestinal-epithelial intrinsic expression of lysine-specific demethylase 1A (LSD1) is necessary for the postnatal maturation of intestinal epithelium as well as maintaining this developed epithelial state in adulthood. Although the stool microbiome was altered in animals with an intestinal-epithelial specific deletion of Lsd1, by depleting the microbial component using antibiotics, we found that the cellular state and number of certain immune cell types were dependent on maturation of the epithelium. We found plasma cells, innate lymphoid cells (ILCs), and a specific myeloid population to be depending on epithelial LSD1 expression. We propose that LSD1 controls the expression of epithelial-derived chemokines, such as Cxcl16, and this is a mode of action for this epithelial-immune cell interplay. For example, we show that LSD1-mediated epithelial-intrinsic CXCL16 controls the number of local ILC2s but not ILC3s. Together, our findings suggest that the maturing epithelium plays a dominant role in regulating the local immune cell composition, thereby contributing to gut homeostasis.

immunology↗

bioRxiv2023

CD163 and Tim-4 identify resident intestinal macrophages across sub-tissular regions that are spatially regulated by TGF-β

In bodily organs, macrophages are localised in poorly understood tissular and sub-tissular niches associated with defined macrophage ontogeny and activity. In the intestine, a paradigm is emerging that long-lived macrophages are dominantly present in the muscular layer, while highly monocyte-replenished populations are found in the lamina propria beneath the epithelial barrier. Whether longevity is restricted in such a simplified manner has not been well explored. Moreover, the impact of specific gut-associated factors on long-lived macrophage functionality and niche occupancy is unknown. We generated sc-RNA-Seq data from wild-type and Ccr2-/- mice to identify phenotypic features of long-lived macrophage populations in distinct intestinal niches and identified CD163 as a useful marker to distinguish submucosal/muscularis (S/M) from lamina propria (LP) macrophages. Challenging the emerging paradigm, long-lived macrophages, identified by Tim-4 expression, were found in the LP and S/M. Long-lived LP macrophages are restrained in their response to proinflammatory stimulation compared to short-lived populations in the same location, and to the long-lived population within the S/M. Employing a novel Timd4creTgfbr2fl/fl mouse line we demonstrate distinct functions of TGF-{beta} on long-lived macrophages in these two compartments. Importantly, in Timd4creTgfbr2fl/fl mice, zonation of CD163+ macrophages in the S/M was lost, suggesting TGF-{beta} plays an unappreciated role in positioning of macrophages in the tissue. These data highlight the importance of considering ontogeny and niche when assessing the action of key intestinal regulatory signals.

immunology↗

bioRxiv2023

A subset of CD4+ effector memory T cells limit immunity to pulmonary viral infection and prevent tissue pathology via activation of latent TGFβ

A rapid immune response to pathogen re-exposure underpins immunological memory, with protection against divergent pathogens such as heterologous or novel viral strains requiring cross-reactive memory T cells. Understanding the pathways that control memory T cell function is therefore important for the rational design of viral vaccines and will aid the discovery of therapies to boost anti-viral immunity. Here, we identify a sub-population of memory T cells that limit secondary immune responses to viral re-infection, which is crucial in preventing host tissue damage. We show that a population of CD4+ effector memory T (TEM) cells activate the important immunoregulatory cytokine TGF{beta}, via expression of an integrin, v{beta}8. Integrin v{beta}8 expression marks a transcriptionally distinct sub-population of CD4+ TEM, enriched for anti-inflammatory pathways. Loss of integrin v{beta}8 on murine CD4+ TEM, but not Foxp3+ regulatory T cells (TREG), led to exacerbated virus-specific CD8+ T cell responses following secondary influenza A virus (IAV) infection, which was associated with enhanced viral clearance. However, although accelerating clearance, loss of integrin v{beta}8 expression on CD4+ TEM resulted in enhanced lung pathology following secondary IAV infection, which was completely reversed by adoptive transfer of v{beta}8+ CD4+ TEM cells. These data highlight a new pathway by which a distinct CD4+ memory T cell subset restrains anti-viral immunity to prevent host tissue damage during secondary viral infection. Such pathways could be targeted therapeutically to either boost memory T-cell-mediated immunity or restrain host tissue damage during viral infection.

immunology↗

bioRxiv2020

Ongoing exposure to peritoneal dialysis fluid alters resident peritoneal macrophage phenotype and activation propensity

Peritoneal dialysis (PD) is a more continuous alternative to haemodialysis, for patients with chronic kidney disease, with considerable initial benefits for survival, patient independence and healthcare costs. However, longterm PD is associated with significant pathology, negating the positive effects over haemodialysis. Importantly, peritonitis and activation of macrophages is closely associated with disease progression and treatment failure. However, recent advances in macrophage biology suggest opposite functions for macrophages of different cellular origins. While monocyte-derived macrophages promote disease progression in some models of fibrosis, tissue resident macrophages have rather been associated with protective roles. Thus, we aimed to identify the relative contribution of tissue resident macrophages to PD induced inflammation in mice. Unexpectedly, we found an incremental loss of homeostatic characteristics, anti-inflammatory and efferocytic functionality in peritoneal resident macrophages, accompanied by enhanced inflammatory responses to external stimuli. Moreover, presence of glucose degradation products within the dialysis fluid led to markedly enhanced inflammation and almost complete disappearance of tissue resident cells. Thus, alterations in tissue resident macrophages may render longterm PD patients sensitive to developing peritonitis and consequently fibrosis/sclerosis.

immunology↗