Biology subjects

Kedl, R. M.

Publications and source records attributed to Kedl, R. M..

4 recordsLinked to original sources

bioRxiv2025

GPR182 is a lipoprotein receptor for dietary fat absorption

The lymphatic system plays a central role in lipid absorption, which transports chylomicrons from the small intestine to the circulation. However, the molecular mechanism by which chylomicrons get into the intestinal lymphatics is unknown. Here we demonstrated that GPR182, a receptor in lymphatic endothelial cells (LECs), mediates dietary fat absorption. GPR182 knockout mice are resistant to dietary-induced obesity. GPR182 ablation in mice leads to poor lipid absorption and thereby a delay in growth during development. GPR182 binds and endocytoses lipoproteins broadly. Mechanistically, loss of GPR182 prevents chylomicrons from entering the lacteal lumen of the small intestine. GPR182 blockage with a monoclonal antibody (mAb) protects mice from dietary induced obesity. Together, our study identifies GPR182 as a lipoprotein receptor that mediates dietary fat absorption.

physiology↗

bioRxiv2025

The type I IFN-IL-27 axis promotes mRNA vaccine-induced CD8+ T cell responses

The ability of lipid nanoparticle (LNP)-delivered mRNA vaccines to induce type I IFNs is critical to promote CD8+ T cell responses. The studies presented here indicate that immunization with nucleoside modified mRNA-LNP vaccines drives myeloid cell expression of the cytokine IL-27, which acts on antigen-specific CD8+ T cells to sustain T cell expansion. In vitro and in vivo studies revealed that type I IFN signaling is necessary for mRNA-LNP-induced IL-27 production, that immunization failed in IL-27 KO mice, and that immunization of IFNAR1-deficient mice with mRNA-LNP particles that also encode IL-27 mRNA restored antigen-specific CD8+ T cell responses. In addition, IL-27 mRNA-LNPs served as an adjuvant that improved cytolytic CD8+ T cell responses and the therapeutic efficacy of mRNA-LNPs to drive anti-pathogen and anti-tumor immunity. These studies highlight the central role of IL-27 in mRNA-LNP induced CD8+ T cell responses and the ability of this cytokine to augment the functionality of the CD8+ T cell response for prophylactic or therapeutic immunization.

immunology↗

bioRxiv2024

IL-27 Stablizes Myc-Mediated Transcription In Memory-Fated, Vaccine-Elicited CD8+ T Cells

Protection from pathogens relies on both humoral (antibody-mediated) and cellular (T cell-mediated) responses. While infections robustly elicit both types of immunity, currently approved vaccine adjuvants largely fail to induce T cell responses on par with that instigated by infections. Our goal was to investigate the transcriptional programming that supports the formation of CD8+ T cells elicited by subunit vaccines compared to those elicited by infections. Our data show that vaccine-elicited T cells represent a transcriptionally unique subset of activated T cells with high proliferative capacity and a memory cell fate. This relies on IL-27 signaling, which stabilizes c-Myc and thereby supports the biomass acquisition necessary for clonal expansion. Collectively, our findings reveal that subunit vaccine-elicited T cells uniquely combine aspects of both memory and effector T cell subsets, and selectively utilize IL-27 signaling to sustain the clonal expansion of cells dedicated to a memory fate. One Sentence SummaryIn contrast to infection, subunit vaccines induce a distinct population of CD8+ T cells with memory fate characteristics which maintain their proliferative capacity during the expansion phase through IL-27 receptor signaling.

immunology↗

bioRxiv2020

cDC1 Coordinate Innate and Adaptive Responses in the Omentum required for T cell Priming and Memory

The omentum in the peritoneal cavity contains fat associated lymphoid clusters (FALCs) whose role in the response to microbial challenge are poorly understood. After intraperitoneal immunization with Toxoplasma gondii, type I dendritic cells (cDC1) were critical to induce innate sources of IFN-{gamma} required to recruit monocytes to the FALCs. The migration of infected peritoneal macrophages into T and B cell rich areas of the FALCs allowed the TCR-induced activation of parasite-specific T cells. Unexpectedly, cDC1 were not required for T cell priming but rather supported the expansion of parasite-specific CD8+ T cells. An agent-based mathematical model predicted that the lack of cDC1 would impact the early proliferative burst, and we confirmed that cDC1 were required for optimal T cell expression of nutrient uptake receptors and cell survival. These studies highlight that cDC1 in the FALCs have distinct roles in the co-ordination of the innate and adaptive responses to microbial challenge.

immunology↗