Project description:Ketone bodies are essential alternative fuels that allow humans to survive periods of glucose scarcity induced by starvation and prolonged exercise. A widely used ketogenic diet (KD), that is extremely high in fat with very-low carbohydrates, drives the host into using β-hydroxybutyrate (BHB) for the production of ATP and lowers NLRP3-mediated inflammation. However, the extremely high fat composition of KD raises the question of how ketogenesis impacts adipose tissue to control inflammation and energy homeostasis. Using single-cell RNA sequencing of adipose tissue-resident immune cells, we identified that KD expands metabolically protective γδ T cells that restrain inflammation. However, a long-term KD caused obesity, impaired metabolic health and depleted the adipose resident γδ T cells. Moreover, mice lacking γδ T cells have impaired glucose homeostasis. We conclude that γδ T cells are mediators of protective immunometabolic responses that link fatty acid driven fuel utilization to reduced adipose tissue inflammation.
Project description:Ketone bodies are essential alternative fuels that allow humans to survive periods of glucose scarcity induced by starvation and prolonged exercise. A widely used ketogenic diet (KD), that is extremely high in fat with very-low carbohydrates, drives the host into using β-hydroxybutyrate (BHB) for the production of ATP and lowers NLRP3-mediated inflammation. However, the extremely high fat composition of KD raises the question of how ketogenesis impacts adipose tissue to control inflammation and energy homeostasis. Using single-cell RNA sequencing of adipose tissue-resident immune cells, we identified that KD expands metabolically protective γδ T cells that restrain inflammation. However, a long-term KD caused obesity, impaired metabolic health and depleted the adipose resident γδ T cells. Moreover, mice lacking γδ T cells have impaired glucose homeostasis. We conclude that γδ T cells are mediators of protective immunometabolic responses that link fatty acid driven fuel utilization to reduced adipose tissue inflammation.
Project description:Influenza A virus (IAV) infection-associated morbidity and mortality are a key global healthcare concern, necessitating the identification of novel therapies capable of reducing the severity of IAV infections. In this study, we show that the consumption of a low-carbohydrate, high-fat ketogenic diet (KD) protects mice from lethal IAV infection and disease. KD feeding resulted in an expansion of γδ T cells in the lung that improved barrier functions, thereby enhancing anti-viral resistance. Expansion of these protective γδ T cells required metabolic adaptation to a ketogenic diet, as neither feeding mice a high-fat high-carbohydrate diet nor providing chemical ketone body substrate that bypasses hepatic ketogenesis protected against infection. Therefore, KD mediated immune-metabolic integration represents a viable avenue towards preventing or alleviating influenza disease.
Project description:Influenza infection causes high rates of hospitalization and mortality in infants. γδ T cells are critical for immune responses against pathogens as regulators and effectors, especially in infants, and yet the roles of neonatal γδ T cells in influenza remain to be investigated. Here we report that γδ T cells were protective against mortality associated with neonatal influenza infection. Infection induced the accumulation and activation of γδ T cells, which transiently expressed IL-17a to enhance early IL-33 production by lung epithelial cells via STAT3 phosphorylation. Subsequently, this led to type 2 immune responses with elicited infiltration of ILC2s and Tregs resulting in increased amphiregulin secretion and tissue repair. Loss of γδ T cells did not alter viral clearance or IFN-γ production. Thus, our results identify a specific requirement for γδ T cells in influenza-infected neonates by initiating type 2 immune responses, mediating tissue homeostasis, and promoting lung integrity.
Project description:The mammalian gastrointestinal tract harbors thousands of bacterial species that include symbionts as well as potential pathogens. The immune responses that limit access of these bacteria to underlying tissue remain poorly defined. In this study, we used microarrays to uncover the transcriptional responses that occur in small intestinal γδ intraepithelial lymphocytes following bacterial challenge. γδ intraepithelial lymphocytes (γδ IEL) were isolated by flow cytometry from the small intestines of germ-free mice, or from age- and sex-matched conventionally-raised counterparts. We extracted RNAs from these purified γδ IEL for analysis on Affymetrix DNA microarrays. The mice were all >8 weeks in age, and each sample represents a pool of RNAs from 5-8 mice.