No abstract

T cells must tightly regulate their metabolic processes to cope with varying bioenergetic demands depending on their state of differentiation. The metabolic sensor AMPK is activated in states of low energy supply and modulates cellular metabolism toward a catabolic state. Although this enzyme is known to be particularly active in regulatory T (T) cells, its impact on T helper (T)-cell differentiation is poorly understood. We investigated the impact of several AMPK activators on T-cell differentiation and found that the direct activator AICAR (5-aminoimidazole-4-carboxamide ribonucleotide), but not the indirect activators metformin and 2-deoxyglucose, strongly enhanced T-cell induction by specifically enhancing T-cell expansion. Conversely, T17 generation was impaired by the agent. Further investigation of the metabolic background of our observations revealed that AICAR enhanced both cellular mitochondrogenesis and fatty acid uptake. Consistently, increased T induction was entirely reversible on inhibition of fatty acid oxidation, thus confirming the dependence of AICAR's effects on metabolic pathways alterations. Translating our findings to an in vivo model, we found that the substance enhanced T cell generation on IL-2 complex-induced immune stimulation. We provide a previously unrecognized insight into the delicate interplay between immune cell function and metabolism and delineate a potential novel strategy for metabolism-targeting immunotherapy.-Gualdoni, G. A., Mayer, K. A., Göschl, L., Boucheron, N., Ellmeier, W., Zlabinger, G. J. The AMP analog AICAR modulates the T/T17 axis through enhancement of fatty acid oxidation.

No abstract

Molecular mechanisms that maintain lineage integrity of helper T cells are largely unknown. Here we show histone deacetylases (HDAC) 1 and 2 as crucial regulators of this process. Loss of HDAC1 and HDAC2 during late T cell development led to the appearance of MHC class II-selected CD4+ helper T cells (TH) that expressed CD8 lineage genes such as Cd8a and Cd8b1. HDAC1-HDAC2-deficient TH0 and TH1 cells further up-regulated Cd8 lineage genes and acquired a CD8 effector program in a manner dependent on Runx-CBFβ complexes, while TH2 cells repressed CD8 lineage features independently of HDAC1 and HDAC2. These results demonstrate that HDAC1-HDAC2 maintain CD4 lineage integrity by repressing Runx-CBFβ complexes that otherwise induce a CD8-like effector program in CD4+ T cells.