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Single cell gene expression profile of WT and Opa1 knockout OT-I T cells

ABSTRACT: The goal of our study was to compare the gene expression of both naïve and activated T cells deficient in the mitochondrial protein Optic atrophy 1 (Opa1) using single cell RNA sequencing. A growing amount of evidence has begun to illustrate that the requirements driving effector- and memory-destined CD8 T cells during an infection are not shared with adjuvanted vaccine responses. Short-lived effector cells are characterized metabolically by a highly glycolytic state driving energy and biomass production whereas vaccine-elicited T cells can meet these requirements through mitochondrial metabolism. Here we show that the mitochondrial protein Optic atrophy 1 (Opa1) is critical for rapidly dividing CD8 T cells in vivo. This requirement, contrary to prior published data, is most pronounced in effector CD8 T cells. More specifically, Opa1 supports proper cell cycle initiation, progression, and supports the viability and survival of CD8 T cells during immune responses to both infections and vaccine challenges

ORGANISM(S): Mus musculus

PROVIDER: GSE263898 | GEO | 2025/04/12

REPOSITORIES: GEO

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Project description:T helper 17 (Th17) cells are a distinct subset of CD4+ T cells necessary for maintaining gut homeostasis and have prominent roles in autoimmunity and inflammation1. Th17 cells have unique metabolic features, including a stem cell-like signature2,3 and reliance on mitochondrial respiratory chain function and tricarboxylic acid (TCA) cycle to coordinate metabolic and epigenetic remodeling4,5. Dynamic changes in mitochondrial membrane morphology are key to sustain organelle function6. However, it remains unclear whether mitochondrial membrane remodeling orchestrates metabolic and differentiation events in Th17 cells. Here we demonstrate that mitochondrial membrane fusion and tight cristae organization are required for Th17 cell function (i.e. cytokine expression) but dispensable in other T cell subsets. We find that Th17 cells rely on mitochondrial fusion as a result of their low metabolic activity. Thus, lowering metabolic activity in other T cell subsets by nutrient restriction was sufficient to increase reliance on mitochondrial fusion for effector function. Transcriptional, proteomic, and metabolomic profiling identified the serine/threonine kinase liver associated kinase B1 (LKB1) as an essential node coupling mitochondrial function to cytokine expression in T cells. By genetic and metabolomic approaches, we demonstrate that LKB1 regulates IL-17A expression by controlling TCA cycle metabolites and transcriptional remodeling. Th-17 cell-specific deletion of optic atrophy 1 (OPA1), a protein involved in mitochondrial inner membrane fusion and cristae organization, reduced autoimmune pathogenesis in a mouse model of multiple sclerosis, while additional deletion of LKB1 restored disease. Our findings highlight distinct mitochondrial requirements in CD4+ T cells, identify mitochondrial membrane fusion as a major determinant of Th17 responses, and reveal LKB1 as a sensor of mitochondrial integrity that links mitochondrial cues to effector programs in Th17 cells.

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Single cell gene expression profile of WT and Opa1 knockout OT-I T cells

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