Biology subjects

Olsen, T. M.

Publications and source records attributed to Olsen, T. M..

5 recordsLinked to original sources

bioRxiv2026

Coincident epithelial signals restrain commensal-specific CD8αβ+ T cells in the intestine

The intestinal epithelium harbors a large population of microbiota-dependent CD8{beta}+ T cells whose antigen specificity and regulation are ill-defined. By identifying MHCIa-restricted TCRs and generating tetramers against the gut commensal Segmented Filamentous Bacteria, we demonstrate that a single commensal species drives a clonally expanded, antigen-specific CD8{beta}+ T cell within the intraepithelial lymphocyte compartment. Mechanistically, the intestinal epithelium coordinates coincident signals governing this population: peptide:MHC-dependent TCR engagement drives pIEL accumulation, while v{beta}6-mediated TGF{beta} activation restraints effector cell differentiation. Perturbation of epithelial cell-mediated TGF{beta} activation diverts commensal-specific CD8+ T cells toward inflammatory differentiation states transcriptionally convergent with those observed in ulcerative colitis. The intestinal epithelium thus functions as a dual-signal organizer of commensal-specific CD8+ T cell responses, coupling differentiation to restraint through spatially coincident molecular cues.

immunology↗

bioRxiv2025

Hypoxia-inducible factor 2α promotes protective Th2 cell responses during intestinal helminth infection

Th2 cells must sense and adapt to the tissue milieu in order to provide protective host immunity and tissue repair. Here, we examined the mechanisms promoting Th2 cell differentiation and function within the small intestinal lamina propria. Single cell RNA-seq analyses of CD4+ T cells from the small intestinal lamina propria of helminth infected mice revealed high expression of the gene Epas1, encoding the transcription factor hypoxia-inducible factor 2a (HIF2). In vitro, exposure to hypoxia or genetic HIF2 activation promoted Th2 cell differentiation, even under non-polarizing conditions. In mice, HIF2 activation in CD4+ T cells promoted intestinal Th2 cell accumulation in the absence of infection, and HIF2-deficiency impaired CD4+ T cell-mediated host immunity to intestinal helminth infection. Our findings identified hypoxia, and the oxygen-regulated transcription factor Hypoxia-Inducible Factor 2 (HIF2), as key regulators of Th2 cell differentiation and function within the small intestine.

immunology↗

bioRxiv2024

A type 1 immune-stromal cell network mediates disease tolerance and barrier protection against intestinal infection

Type 1 immunity mediates host defense through pathogen elimination, but whether this pathway also impacts tissue function is unknown. Here we demonstrate that rapid induction of IFN{gamma} signaling coordinates a multi-cellular response that is critical to limit tissue damage and maintain gut motility following infection of mice with a tissue-invasive helminth. IFN{gamma} production is initiated by antigen-independent activation of lamina propria CD8+ T cells following MyD88-dependent recognition of the microbiota during helminth-induced barrier invasion. IFN{gamma} acted directly on intestinal stromal cells to recruit neutrophils that limited parasite-induced tissue injury. IFN{gamma} sensing also limited the expansion of smooth muscle actin-expressing cells to prevent pathological gut dysmotility. Importantly, this tissue-protective response had limited impact on parasite burden, indicating that IFN{gamma} supports a disease tolerance defense strategy. Our results have important implications for managing the pathophysiological sequelae of post-infectious gut dysfunction and chronic inflammatory diseases associated with stromal remodelling. HIGHLIGHTSO_LIType 1 immunity is required for disease tolerance to tissue-invasive infection. C_LIO_LIGut-resident CD8+ T cells produce IFN{gamma} in an antigen-independent, yet microbiota-dependent manner. C_LIO_LIIFN{gamma} signaling recruits neutrophils in a cell-extrinsic manner to limit helminth-induced tissue injury. C_LIO_LIDirect sensing of IFN{gamma} by intestinal stroma is essential to limit tissue damage and maintain gut motility during infection. C_LI

immunology↗

bioRxiv2023

Antigen-level resolution of commensal-specific B cell responses enabled by phage-display screening and B cell tetramers

Induction of adaptive immune responses to commensal microbes is critical for tissue homeostasis, and perturbation of these responses is associated with multiple chronic inflammatory disorders. However, the mechanisms underlying the induction and regulation of mucosal B cells targeting commensal microbes remain poorly understood, in part due to a lack of tools to identify commensal-specific B cells ex vivo. To address this, we identified immunogenic protein epitopes recognized by Segmented Filamentous Bacteria (SFB)-specific serum antibodies using a whole-genome phage display screen and identified immunogenic proteins engaging IgA, IgG1 and IgG2b responses. Using these antigens, we generated B cell tetramers to identify and track SFB-specific B cell responses in the gut associated lymphoid tissue during natural and de novo colonization. We revealed a compartmentalized response in SFB-specific B cell activation between Peyers patches and mesenteric lymph nodes, with a gradient of IgA, IgG1 and IgG2b isotypes along the small intestine, and selective production of IgG2b with the mesenteric lymph node chain. VDJ sequencing analyses and generation of SFB-specific monoclonal antibodies identified that somatic hypermutation drives affinity maturation to SFB derived antigens under homeostatic conditions. By combining phage display screening and B cell tetramer technologies, we now enable antigen-level based studies of immunity to intestinal microbes, which will advance our understanding of the ontogeny and function of commensal-specific B cell responses in tissue immunity, inflammation and repair.

immunology↗

bioRxiv2021

Pro-apoptotic caspase deficiency reveals a cell-extrinsic mechanism of NK cell regulation

AO_SCPLOWBSTRACTC_SCPLOWRegulated cell death is essential for the maintenance of cellular and tissue homeostasis. In the hematopoietic system, genetic defects in apoptotic cell death generally produce the accumulation of immune cells, inflammation and autoimmunity. In contrast, we found that genetic deletion of caspases of the mitochondrial apoptosis pathway reduces natural killer (NK) cell numbers and makes NK cells functionally defective in vivo and in vitro. Caspase deficiency results in constitutive activation of a type I interferon (IFN) response, due to leakage of mitochondrial DNA and activation of the cGAS/STING pathway. The NK cell defect in caspase-deficient mice is independent of the type I IFN response, but the phenotype is partially rescued by cGAS or STING deficiency. Finally, caspase deficiency alters NK cells in a cell-extrinsic manner. Type I IFNs and NK cells are two essential effectors of antiviral immunity, and our results demonstrate that they are both regulated in a caspase-dependent manner. Beyond caspase-deficient animals, our observations may have implications in infections that trigger mitochondrial stress and caspase-dependent cell death.

immunology↗