Lupus susceptibility gene Esrrg regulates TREG development and suppressive function through mitochondrial metabolism
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ABSTRACT:
PROVIDER: PRJNA631420 | ENA |
REPOSITORIES: ENA
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Project description:To investigate insight into how Esrrg regulates the TREG transcriptional program, we performed high-throughput RNA sequencing (RNA-seq) analysis of CD4+Foxp3-YFP+ from splenic cells of WT and KO female mice (2-3 months old). We show that the Esrrg-deficient Treg cells presented increased transcript related to oxidative phosphoration, cell cycle, proteasome, and antigen-presenting, suggesting Esrrg plays an essential role in mitochondral metabolism and it is associated with antigen-presenting and processing. Finally, Esrrg-deficient Treg displayed decreased Erbb and ribosome pathway, which may also related to TREG function. Our data suggest an critical role of lupus susceptibility gene Esrrg in regulating Treg cell function through mitochondrial metabolism.
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Project description:Regulatory T cells (Tregs) negatively regulate immune-mediated inflammation that is essential for preventing autoimmunity, but which can be detrimental in cancer. Central to Treg activation are changes in lipid metabolism to support their survival and function. Fatty acid binding proteins (FABPs) are a family of lipid chaperones required to facilitate the uptake and trafficking of intracellular lipids. One family member, FABP5, is expressed in certain T cell subsets, but its function remains elusive. We show here that in Tregs, FABP5 inhibition causes mitochondrial defects, underscored by decreased OXPHOS, lipid elongation and desaturation, and loss of cristae structure, which augment their suppressive function. Mitochondrial dysfunction after FABP5 inhibition results in mtDNA release and consequent cGAS/STING-dependent type I IFN signaling, which induces increased production of the regulatory cytokine IL-10, promoting Treg cell suppressive activity. Together these data reveal that FABP5 acts as a gatekeeper of mitochondrial health to control Treg cell function.
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Project description:Lupus susceptibility results from the combined effects of numerous genetic loci, but the contribution of these loci to disease pathogenesis has been difficult to study due to the large cellular heterogeneity of the autoimmune immune response. We performed single cell RNA, B cell receptor (BCR), and T cell receptor (TCR) sequencing of splenocytes from mice with multiple polymorphic lupus susceptibility loci. We not only observed lymphocyte and myeloid expansion, but also characterized changes in subset frequencies and gene expression, such as decreased CD8 and marginal zone B cells and increased Fcrl5 and Cd5l expressing macrophages. Clonotypic analyses revealed expansion of B and CD4 clones, and TCR repertoires from lupus prone mice were distinguishable by algorithmic specificity prediction and unsupervised machine learning classification. Myeloid differential gene expression, metabolism, and altered ligand-receptor interaction were associated with decreased antigen presentation. This dataset provides novel mechanistic insight into the pathophysiology of a spontaneous model of lupus, highlighting potential therapeutic targets for autoantibody mediated disease.
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