Biology subjects

Burchill, M. A.

Publications and source records attributed to Burchill, M. A..

3 recordsLinked to original sources

bioRxiv2025

High Precision Peptide-MHC Class I CARs Enhance In Vivo Killing ofTargeted CD8 T Cells to Prevent Type 1 Diabetes in Novel RIP-mOVA Model

Progress has been made to address refractory T cell-mediated diseases with chimeric antigen receptor (CAR) T cell platforms, with the need more specifically target pathogenic cells being addressed by peptide-MHC (pMHC) CAR T cells. However, progress to date has largely been limited to peptide-MHC Class II (pMHC-II) CARs for the targeting of autoreactive CD4 T cells in multiple models. Here, we develop the first single molecule peptide-MHC Class I-{beta}2 microglobulin CAR platform to demonstrate the proof of concept for depletion of antigen-specific CD8 T cells and compare the in vitro and in vivo functionality to a traditional scFv-based CAR that also targets the TCR. We demonstrate that while the scFv CAR is more rapidly and robustly activated by target CD8 T cells in vitro, the greater precision offered by pMHC-I CARs results in greater efficacy in multiple in vivo models. Additionally, we developed a novel adjuvanted ovalbumin vaccination with adoptive transfer model to induce type 1 diabetes (T1D) in RIP-mOVA mice using a polyclonal, polyepitopic T cell population. We demonstrate that our pMHC-I platform depletes SIINFEKL-reactive T cells and that control of the immune response to the dominant SIINFEKL epitope can control a broader antigenic response.

immunology↗

bioRxiv2024

Antigen-driven CD8+ T cell clonal expansion is a prominent feature of MASH in humans and mice.

Background and AimsChronic liver disease due to metabolic dysfunction-associated steatohepatitis (MASH) is a rapidly increasing global epidemic. MASH progression is a consequence of the complex interplay between inflammatory insults and dysregulated hepatic immune responses. T lymphocytes have been shown to accumulate in the liver during MASH, but the cause and consequence of T cell accumulation in the liver remain unclear. Our study aimed to define the phenotype and T cell receptor diversity of T cells from human cirrhotic livers and an animal model of MASH to begin resolving their function in disease. Approach and ResultsIn these studies, we evaluated differences in T cell phenotype in the context of liver disease we isolated liver resident T cell populations from individuals with cirrhosis and a murine model of MASH. Using both 5 single cell sequencing and flow cytometry we defined the phenotype and T cell receptor repertoire of liver resident T cells during health and disease. ConclusionsMASH-induced cirrhosis and diet-induced MASH in mice resulted in the accumulation of activated and clonally expanded T cells in the liver. The clonally expanded T cells in the liver expressed markers of chronic antigenic stimulation, including PD1, TIGIT and TOX. Overall, this study establishes for the first time that T cells undergo antigen-dependent clonal expansion and functional differentiation during the progression of MASH. These studies could lead to the identification of potential antigenic targets that drive T cell activation, clonal expansion, and recruitment to the liver during MASH.

immunology↗

bioRxiv2024

NF-kB/NLRP3 Translational Inhibition by Nanoligomer Therapy Mitigates Ethanol and Advanced Age-Related Neuroinflammation

Binge alcohol use is increasing among aged adults (>65 years). Alcohol-related toxicity in aged adults is associated with neurodegeneration, yet the molecular underpinnings of age-related sensitivity to alcohol are not well described. Studies utilizing rodent models of neurodegenerative disease reveal heightened activation of Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-{kappa}B) and Nod like receptor 3 (NLRP3) mediate microglia activation and associated neuronal injury. Our group, and others, have implicated hippocampal-resident microglia as key producers of inflammatory mediators, yet the link between inflammation and neurodegeneration has not been established in models of binge ethanol exposure and advanced age. Here, we report binge ethanol increased the proportion of NLRP3+ microglia in the hippocampus of aged (18-20 months) female C57BL/6N mice compared to young (3-4 months). In primary microglia, ethanol-induced expression of reactivity markers and NLRP3 inflammasome activation were more pronounced in microglia from aged mice compared to young. Making use of an NLRP3-specific inhibitor (OLT1177) and a novel brain- penetrant Nanoligomer that inhibits NF-{kappa}B and NLRP3 translation (SB_NI_112), we find ethanol- induced microglial reactivity can be attenuated by OLT1177 and SB_NI_112 in microglia from aged mice. In a model of intermittent binge ethanol exposure, SB_NI_112 prevented ethanol-mediated microglia reactivity, IL-1{beta} production, and tau hyperphosphorylation in the hippocampus of aged mice. These data suggest early indicators of neurodegeneration occurring with advanced age and binge ethanol exposure are NF-{kappa}B- and NLRP3-dependent. Further investigation is warranted to explore the use of targeted immunosuppression via Nanoligomers to attenuate neuroinflammation after alcohol consumption in the aged.

neuroscience↗