Increased mTORC2 activity in naive T cells from older adults impairs asymmetric cell division 2309021

Abstract Introduction The ability of the adaptive immune system to have memory of previous pathogen encounters is the basis for vaccination as one of the most successful medical interventions. With increasing age, the ability to develop protective immunity after vaccination declines. Differentiation into T memory cells is at least in part determined during the early cell divisions after activation when cells undergo assymmetric cell division (ACD). Fate decisions depend on the uneven distribution of signaling molecules and transcription factors with accumulation of mTORC1 activity biasing for an effector and TCF1 for a memory state. We explored whether ACD of naïve CD4 T cells is impaired in older adults. Methods We used human primary cells from young and older adults. Human naive CD4 T cells were isolated and cultured in RPMI, 10% FBS and antibiotics on plates coated with anti-CD3 Ab, anti-CD28 Ab and huICAM1 for 3 days. We used transfection by electroporation to modify gene expression. Read out systems included confocal microscopy, flow cytometry and lysosome function assays. Results were compared by t-test with values of p < 0.05 considered significant. Results Naive CD4 T cell responses from older adults is characterized by increased activation of the AKT-mTORC1 pathway and reduced ACD of mTORC1 activity. Increased RICTOR expression resulting in increased mTORC2 activity in naive CD4 T cells from older individuals accounted for the activation of the AKT-mTORC1 pathway. AKT inhibition or silencing of RICTOR restores ACD of mTORC1 activity as well as of TCF1. Conversely, ACD was also improved through inducing WNT signaling by GSK3β inhibition irrespective of RICTOR expression. Conclusion Our data show that increased RICTOR expression in naïve T cells from older adults at least in part accounts for defective memory cell generation. Silencing of RICTOR or downstream AKT inhibition can enforce both mTORC1 ACD and TCF1 ACD suggesting that mTORC2 is a promising target to improve vaccine responses. Funding Source n/a Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)