Biology subjects

Hincks, J.

Publications and source records attributed to Hincks, J..

3 recordsLinked to original sources

bioRxiv2026

CD11c+ microglia promote dysfunctional T cell activation in diffuse midline glioma

Paediatric diffuse midline glioma (DMG) remains refractory to immunotherapy despite T-cell infiltration, indicating that local mechanisms actively suppress anti-tumour immunity. Using complementary genetic and orthotopic mouse models, we performed lineage-resolved profiling of the DMG immune microenvironment, resolving myeloid ontogeny and microglial states by distinguishing resident microglia from infiltrating bone marrow-derived macrophages. We identified microglia as the predominant tumour-associated myeloid population and discovered selective expansion of CD11c positive; microglia exhibiting enriched antigen-presentation and immune-regulatory transcriptional programs. Tumour-infiltrating CD4+; and CD8+; T cells exhibited chronic activation and exhaustion, while ligand receptor analysis predicted inhibitory microglia T cell communication. Pharmacological CSF1R inhibition depleted CD11c positive; microglia, attenuated antigen-presentation and immune-regulatory programs, and shifted tumour-infiltrating T cells toward a less exhausted phenotype. Together, these findings identify a previously unrecognised CD11 positive; microglia T-cell axis that establishes immune dysfunction in DMG and provide a rationale for combining myeloid- and T cell-targeted immunotherapies.

cell biology↗

bioRxiv2026

Microbiota-sensitive glial and metabolic programs define a critical window in early postnatal brainstem development

Paediatric brain tumours are increasingly recognised as diseases of disrupted development, arising when lineage progression programs, that normally govern neural and glial maturation, become stalled or dysregulated. Diffuse midline glioma (DMG), a highly aggressive paediatric brainstem tumour, emerges during early childhood in the pons, a region undergoing rapid postnatal growth characterized by oligodendrocyte precursor cell (OPC) proliferation and differentiation. However, the environmental factors that shape these developmental trajectories remain poorly defined. Here, using germ-free and conventionally colonized mice, we investigated whether early-life microbiota influences transcriptional and metabolic programs in the developing brainstem during this critical developmental window. Bulk RNA sequencing revealed pronounced microbiota-associated transcriptional differences at postnatal day 2 (P2), but not at P8, identifying a temporally restricted period during which microbial colonization is associated with pathways linked to oligodendrocyte lineage progression, myelination, and neuroimmune signalling. Transcriptional analyses further identified altered expression of genes associated with CD11c microglia, a developmental microglial subtype implicated in regulating oligodendrocyte maturation. Untargeted metabolomic profiling revealed parallel microbiota-associated differences in pathways related to mitochondrial function, redox balance, and methyl-donor metabolism. Integrated multi-omics analyses identified coordinated networks linking glial lineage programs with metabolites involved in cellular metabolism and epigenetic regulation. Notably, several of these transcriptional and metabolic programs overlap with gene signatures reported in diffuse midline glioma, suggesting that microbiota-sensitive developmental pathways intersect with cellular states relevant to paediatric brainstem tumour biology.

neuroscience↗

bioRxiv2021

Exposure to nitric oxide drives transition to resuscitation-promoting factor-dependency in mycobacteria

During infection Mycobacterium tuberculosis (Mtb) forms differentially culturable (DC) subpopulations that are recalcitrant to treatment and undetectable using standard diagnostic tools. DC Mtb are revealed in liquid media, their revival is often stimulated by resuscitation-promoting factors (Rpfs), secreted peptidoglycan-remodelling enzymes, and prevented by Rpf inhibitors. Here we investigated the role of nitric oxide (NO) in generation of Rpf- dependent DC Mtb, using murine macrophage infection models and treatment with a synthetic NO donor (NOD). Mtb subpopulations were assessed by colony-forming unit counting on agar or by limiting dilution Most Probable Number assays in liquid media with or without Rpf inhibitor. Rpf-dependent DC Mtb were detected following infection of interferon-{gamma} induced macrophages capable of producing NO, but not when iNOS was inactivated. NOD treatment also induced transition to the Rpf-dependent DC phenotype which was accompanied by global transcriptomic changes resulting in the dramatic down-regulation of rpfA-E gene expression. Furthermore, the DC phenotype was partially reverted by artificial over-expression of Rpfs. This study elucidates molecular mechanisms underlying the generation of DC Mtb, which are the dominant population recovered from clinical tuberculosis samples, with implications for improving both tuberculosis diagnostics and treatments.

microbiology↗