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Alpha-ketoglutarate induces lipidome remodeling and mitochondrial metabolism to inhibit regulatory T cell differentiation

ABSTRACT: The differentiation of CD4 T cells is regulated by glycolysis and mitochondrial oxidative phosphorylation (OXPHOS), integrating the cell’s metabolism with transcriptional and epigenetic changes. However, the precise mechanisms coupling tricarboxylic (TCA) acid cycle intermediates to CD4 T cell differentiation remain unclear. Here we demonstrate that a-ketoglutarate (aKG) increased Th1 polarization while significantly inhibiting regulatory T cell (Treg) generation. Consistent with these data, aKG promoted the effector profile of Treg-polarized chimeric antigen receptor-engineered T cells against the ErbB2 tumor antigen. Mechanistically, aKG altered the transcription of >250 membrane-related genes, decreasing membrane fluidity and inducing a robust lipidome-wide remodelling. The massive increase in storage and mitochondria lipids was associated with a significantly augmented OXPHOS. Notably, inhibition of succinate dehydrogenase activity, the bridge between the TCA cycle and the electron transport chain, enforced Treg generation. Thus, our study identifies novel connections between aKG, lipidome remodeling and OXPHOS in CD4 T cell fate decisions.

ORGANISM(S): Mus musculus

PROVIDER: GSE156827 | GEO | 2021/09/13

REPOSITORIES: GEO

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Project description:Tumors express a wide variety of both mutated and non-mutated antigens. Whether these tumor antigens are broadly recognized as âselfâ or âforeignâ by the immune system is currently unclear. Using an autochthonous prostate cancer model in which hemagglutinin (HA) is specifically expressed in the tumor (ProHA x TRAMP mice), as well as an analogous model wherein HA is expressed in normal tissues as a model self-antigen (C3HAHigh), we examined the transcriptional profile of CD4 T cells undergoing antigen-specific division. Consistent with our previous data, transfer of antigen-specific CD4 T cells into C3HAHigh resulted in a functionally inactivated CD4 T cell profile. Conversely, adoptive transfer of an identical CD4 T cell population into ProHA x TRAMP resulted in the induction of a regulatory phenotype (Treg) both at the transcriptional and functional level. Interestingly, this Treg skewing was a property of even early-stage tumors, suggesting Treg induction as an important tolerance mechanism during tumor development. The goal of this microarray is to detail the transcriptional profile differences between CD4 T cells that recognize their cognate antigen in the context of tumor (ProHA x TRAMP model) or self-antigen recognition (C3HA) or viral-antigen recognition (VaccHA) models or unprimed naÃ¯ve state (Nontransgenic). The comparison contains both upregulated and downregulated transcripts. Experiment Overall Design: TCR transgenic CD4 T cells specific for hemagglutinin (HA) were adoptively transferred into tumor-antigen recognition model (ProHA x TRAMP), Self-antigen recognition model (C3HA), viral-antigen recognition model (VaccHA), and naÃ¯ve control (Nontrangenic). Divided (CFSE diluted) CD4 T cells were sorted by FACS, RNA was extracted, and biological replicated were hybridized to an Affymetrix Mouse 430 Plus 2 expression array, followed by interrogation with an Affymetrix GeneChip Scanner 3000. RMA normalization was employed to identify differentially expressed transcripts.

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Alpha-ketoglutarate induces lipidome remodeling and mitochondrial metabolism to inhibit regulatory T cell differentiation

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