Bcl-3 regulates the function of Th17 cells through raptor mediated glycolysis metabolism

Bcl-3 is an atypical I kappa B family member that regulates transcription in the nucleus by binding to the p50/p52 homologous dimer subunit. Although various studies illustrate the important role of Bcl-3 in physiological function, its role in metabolism is still unclear. We found that Bcl-3 has a metabolic regulatory effect on autoimmunity. Bcl-3-depleted mice are unable to develop experimental autoimmune encephalomyelitis. The disease resistance was linked to an increase in lactate levels in Th17 cells, and lactate could alleviate EAE development in WT mice. Bcl-3 deficient mice had more differentiated Th17 cells and an increased extracellular acidification rate in these cells. Concurrently, their ultimate respiration rate and respiratory reserve capacity were significantly lower than wild-type mice. However, adding GNE-140 (LADH inhibitor) to Bcl-3-deficient Th17 cells could reverse the phenomenon, and lactate supplementation could increase the glycolysis metabolism of Th17 cells in WT mice. Mechanically, Bcl-3 could interact with Raptor through ANK and RNC domains. Therefore, Bcl-3 regulates Th17 pathogenicity by promoting Raptor mediated energy metabolism, revealing a novel regulation of adaptive immunity.

Automated summary

Bcl-3 is an atypical I kappa B family member that regulates transcription in the nucleus. It has a metabolic regulatory effect on autoimmune diseases, such as experimental autoimmune encephalomyelitis (EAE). Bcl-3 deficiency leads to an increase in lactate levels in Th17 cells, affecting their pathogenicity through energy metabolism regulation.