The CARD11-BCL10-MALT1 (CBM) complex governs activation-induced upregulation of key nutrient transporters and metabolic reprogramming in human CD4+ T cells 3767

Abstract Description Upon activation, CD4+ T cells upregulate multiple nutrient transporters to accommodate cell growth, proliferation, differentiation, and effector function. Nonetheless, molecular pathways that link TCR-dependent signaling to metabolic reprogramming in human T cells remain elusive. Here, we demonstrate a critical role for the scaffold protein CARD11 and associated components in the CBM complex are required in the activation-induced expression of key nutrient transporters in human CD4+ effector T cells, including the glutamine transporter ASCT2 (Slc1a5) and glucose transporter GLUT1 (Slc2a1). Attenuated CBM function coincided with diminished Slc1a5 transcription, while siRNA-mediated knockdown of CBM components markedly reduced TCR/CD28-dependent induction of both receptors, concomitant with impaired glutamine-dependent mTORC1 activation. Inhibiting CBM-dependent pathways such as the MALT1 protease, c-Jun N-terminal kinase (JNK), and mTORC1 decreased TCR/CD28-induced transporter expression over time. The defective expression of ASCT2 and GLUT1 transporters and impaired mTORC1 activation were also detected in CD4+ effector T cells from severe atopic patients harboring dominant-negative (DN) CARD11 mutations. Thus, our findings suggest that the CBM complex is critical for activation-induced nutrient uptake and metabolic calibration in human CD4+ T cells, yielding new insights into the aberrant T cell differentiation and Th2-driven pathogenesis observed in CARD11 DN patients. Funding Sources NIH/NIAID 1R01AI168295 Topic Categories Immune Mechanisms of Human Disease (HUM)