GSE167520
Tcaim delays mitochondria ER contact formation and thereby activation-induced upregulation of anabolism and CD8+ T cell effectr differentiation
T cells need to adapt their cellular metabolism for full effector cell differentiation upon activation and it has been reported that this relies on alterations in mitochondrial physiology including cristae resolution, fission and an increase in membrane potential, mROS production as well as metabolite supply for anabolic pathways. However, which signals and molecules regulate those activation-induced alterations of mitochondria and to which extend inter-organelle communications such as interactions between mitochondria and the ER are required for the change in cellular metabolism still remains unclear. We recently reported that the mitochondrial protein TCAIM is downregulated upon T cell activation and inhibits effector cell differentiation of conventional CD4+ T cells. Our previous investigations also indicated that it interferes with activation-induced changes in mitochondrial morphology and function. Thus, TCAIM seems to function as an important link between activation-induced mitochondrial alterations and changes in cellular metabolism driving full effector cell differentiation. Therefore, we here utilized conditional Tcaim KI and KO mice as a model to investigate which molecular processes at the mitochondria control effector T cell differentiation. First, we could show here that Tcaim KI causes also for CD8+ T cells comparable effects of impaired proliferation, effector/ effector-memory differentiation and cytokine production as we previously reported for CD4+ T cells. Furthermore, our data on Tcaim KO CD8+ T cells point towards an advantage for effector/ effector memory differentiation in vivo. This further supports the regulatory role of TCAIM for activation and differentiation of T cells in general. Metabolomics and transcriptional data indicated that Tcaim KI inhibits activation-induced enforcement of TCA cycle activity and glutaminolysis. More importantly, up-regulation of anabolic pathways, especially of the mevalonate pathway and cholesterol biosynthesis, was blocked upon Tcaim KI. Indeed, addition of cholesterol could rescue T cell activation and proliferation of Tcaim KI CD8+ T cells. At the molecular level, we could show that TCAIM delays activation-induced interaction between mitochondria and the ER, which might be mediated by binding of TCAIM to proteins known to promote MERC formation such as RMD3 and VDAC. Collectively, we provide evidence that TCAIM negatively regulates activation-induced increase in MERC formation and thereby upregulation of anabolic processes, especially towards increased mevalonate pathway and cholesterol biosynthesis, resulting in impaired CD8+ T cell activation and proliferation. Overall design: mRNA expression profiles of naïve and 24 to 48 h polyclonally activated CD8+ T cells from conditional Tcaim KI (n=3), KO (n=2) or wt (n=3) mice by bulk RNA sequencing