Biology subjects

Blackburn, H. N.

Publications and source records attributed to Blackburn, H. N..

4 recordsLinked to original sources

bioRxiv2026

DPP9-mediated inflammasome repression protects against checkpoint inhibitor lung toxicity

Over one million patients receive cancer immunotherapy annually, yet the mechanisms underlying life-threatening immune-mediated toxicities remain poorly understood. Checkpoint inhibitor pneumonitis (CIP) is the leading cause of immunotherapy-related mortality, with a case fatality rate approaching 10%, and no genetic risk factors have been described to date. We identified Dipeptidyl-peptidase 9 (DPP9) as the first genetic susceptibility gene for CIP in a clinico-genomics cohort of 4,397 patients treated with immune checkpoint inhibitors. Mechanistically, DPP9 suppresses CARD8 inflammasome activation and IL-18 secretion in human monocytes, a pathway which is engaged prior to CIP onset, with IL-18 selectively elevated in the plasma of patients who subsequently develop CIP. Myeloid-restricted ablation of Dpp8 and Dpp9 in mice recapitulated the pulmonary histopathological and immunological hallmarks of CIP, including granuloma formation, accumulation of IFN{gamma}-producing T cells and monocyte-derived macrophages. Each of these phenotypes were driven by excessive IL-18 secretion. Together, these findings establish DPP9 as a genetic determinant of CIP and nominate IL-18 blockade as a mechanistically rational therapeutic strategy.

immunology↗

bioRxiv2026

Reverse genetics in humanized mice reveals CARD8-mediated pyroptosis causing pancytopenia in human DPP9 deficiency

Loss of function mutation in the human DPP9 gene causes Hatipoglu syndrome leading to severe inflammasomopathy. A key feature of the disease is pancytopenia and patients require bone marrow transplantation, but the mechanism of cell loss is unclear since Dpp9 mutant mice have normal hematopoiesis, suggesting that a distinct mechanism of disease occurs in humans. Here, we present a model of human DPP9 deficiency leveraging reverse genetics in the MISTRG6 humanized mice. We found that CRISPR editing of human CD34+ hematopoietic stem and progenitor cells (HSPCs) led to very efficient and persistent gene deletion in vivo. Human DPP9 deletion recapitulated cytopenia in peripheral blood and in the bone marrow, and cell loss was cell intrinsic. However, DPP9 deletion led to little transcriptional changes suggesting post-transcriptional regulation in human HSPCs. Mechanistically, DPP9 deficiency led to the activation of the CARD8 inflammasome resulting in HSPC pyroptosis, whereas NLRP1 was dispensable for cell death. Thus, our results reveal a unique human mechanism of disease and offer therapeutic insight for this inflammasomopathy.

immunology↗

bioRxiv2025

FABP5 regulates ether lipid metabolism to ameliorate atopic dermatitis

Atopic dermatitis is an allergic skin disease associated with a profound reorganization of the epidermal lipidome. The effect of the altered lipidome on the skin-resident immune cells that drive disease is unclear. Previous reports identified Fatty acid binding protein 5 (FABP5) as a biomarker for atopic dermatitis, yet how FABP5 might contribute to disease pathogenesis is unknown. Here, we use a murine model of atopic dermatitis, to demonstrate that FABP5 is highly expressed in immune and epithelial cell lineages and that FABP5 protects against skin inflammation. Lipidomic analysis revealed that FABP5 deficiency broadly disrupts the systemic abundance of ether-linked lipids, a minor but important subset of glycerophospholipids. We show that these changes in ether lipid abundance are crucial for the proper regulation of platelet activating factor (PAF), a potent inflammatory ether lipid derivative. Concordantly, we observe elevated PAF in FABP5-deficient mice with dermatitis and that depletion of basophils, a major source of PAF, is sufficient to ameliorate disease in these animals. Altogether, our findings reveal a novel role for FABP5 in the control of allergic inflammation through the modulation of ether lipid and PAF metabolism.

immunology↗

bioRxiv2025

CD8 T cells mediate immunosurveillance for neoantigen+ epithelial stem cells in the colon

Epithelial cells in the colon accumulate substantial numbers of somatic mutations, some of which can be recognised as neoantigens. The ability of CD8 T cells to survey for neoantigen+ cells in the healthy colon would provide an early detection mechanism to prevent cancer, but it is unclear whether neoantigen-specific CD8 T cells can mediate this process of immunosurveillance without becoming tolerant. To address this question, we used a genetically engineered mouse model to express a neoantigen in the epithelial cells of the adult proximal colon. Induction of neoantigen expression led to rapid elimination of neoantigen+ epithelial cells from the colon in a CD8 T cell-dependent manner. Neoantigen-specific CD8 T cells acquired cytolytic function within the colon tissue under steady-state conditions, which was required for elimination of the neoantigen+ epithelial cells. Despite the elimination of [~]25% of their epithelial cells over a two-day period, the colons looked histologically normal. Immunofluorescence and single-cell transcriptomic analyses revealed that neoantigen-specific CD8+ T cells specifically target neoantigen+ stem cells at the crypt base, which was associated with Ki67 in the crypt wall and abundance of neoantigen-negative stem cells. Infiltrating neoantigen-specific CD8 T cells made IFNg and expressed PD-1, raising the question of why PD-1-dependent suppression did not prevent the acquisition of effector functions by these neoantigen-specific CD8 T cells. Despite an increased signature of interferon-stimulated genes in colonic epithelial cells, PD-L1 expression was surprisingly absent. Moreover, we found that colonic epithelial stem cells also did not express PD-L1 under conditions of chronic inflammation, such as ulcerative colitis, immune checkpoint-induced colitis, and ageing, or when directly stimulated with IFN-{gamma} in vitro. Analyses of the PD-L1 gene promoter across humans and mice showed hypermethylation at sites associated with PD-L1 repression in cancer. Thus, our data support a model in which the acquisition of neoantigens by colonic epithelial cells triggers CD8 T cell-mediated immunosurveillance. This results in the elimination of PD-L1-negative neoantigen+ stem cells by effector CD8 T cells and simultaneous repair of the colon by neoantigen-negative epithelial cells to prevent immunopathology.

immunology↗