The AMP analog AICAR modulates the T _reg /T _h 17 axis through enhancement of fatty acid oxidation

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.

Metabolic reprogramming in the tumour microenvironment: a hallmark shared by cancer cells and T lymphocytes

“…Also, metformin pushes the Treg/Th17 balance toward immunosuppressive Treg cells in autoimmune diseases . AICAR, a direct AMPK activator, similarly promotes expansion of Treg cells and reduces Th17 cells by promoting fatty acid oxidation . The implications of metformin treatment on anti‐tumour immunity have yet to be conclusively resolved.…”

Nutrient and Metabolic Sensing in T Cell Responses

“…Aberrant AMPK activation is linked to impaired T FH cell generation in T cells deficient in the ROQUIN RING domain (117). The AMPK agonist, 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), inhibits T H 17 cell induction and promotes T reg cell generation in vitro (118), but these results should be interpreted cautiously due to the reported off-target effects of AICAR (119). Therefore, by sensing energy stress, AMPK plays a pivotal role in metabolic reprogramming to regulate T cell responses.…”

Fasting metabolism modulates the interleukin-12/interleukin-10 cytokine axis

“…Consequently, shifts in immune cell metabolism may be associated with distinct pathologies. However, this can also be envisaged as a tool to redirect unfavourable immune reactivity under pathologic conditions [3, 4]. Among other adaptive mechanisms, inflammation has evolved to maintain physiological homeostasis after microbial challenge of the host.…”