Prosurvival IL-7–Stimulated Weak Strength of mTORC1-S6K Controls T Cell Memory via Transcriptional FOXO1–TCF1–Id3 and Metabolic AMPKα1–ULK1–ATG7 Pathways
Aizhang Xu, Scot C. Leary, Md. Fahmid Islam, Zhaojia Wu, Kalpana K. Bhanumathy, Anjuman Ara, Rajni Chibbar, Andrew Fleywald, Khawaja Ashfaque Ahmed, Jim Xiang
Abstract
Abstract CD8+ memory T (TM) cells play a critical role in immune defense against infection. Two common γ-chain family cytokines, IL-2 and IL-7, although triggering the same mTORC1–S6K pathway, distinctly induce effector T (TE) cells and TM cells, respectively, but the underlying mechanism(s) remains elusive. In this study, we generated IL-7R-/and AMPKα1-knockout (KO)/OTI mice. By using genetic and pharmaceutical tools, we demonstrate that IL-7 deficiency represses expression of FOXO1, TCF1, p-AMPKα1 (T172), and p-ULK1 (S555) and abolishes T cell memory differentiation in IL-7R KO T cells after Listeria monocytogenesis rLmOVA infection. IL-2– and IL-7–stimulated strong and weak S6K (IL-2/S6Kstrong and IL-7/S6Kweak) signals control short-lived IL-7R−CD62L−KLRG1+ TE and long-term IL-7R+CD62L+KLRG1− TM cell formations, respectively. To assess underlying molecular pathway(s), we performed flow cytometry, Western blotting, confocal microscopy, and Seahorse assay analyses by using the IL-7/S6Kweak–stimulated TM (IL-7/TM) and the control IL-2/S6Kstrong–stimulated TE (IL-2/TE) cells. We determine that the IL-7/S6Kweak signal activates transcriptional FOXO1, TCF1, and Id3 and metabolic p-AMPKα1, p-ULK1, and ATG7 molecules in IL-7/TM cells. IL-7/TM cells upregulate IL-7R and CD62L, promote mitochondria biogenesis and fatty acid oxidation metabolism, and show long-term cell survival and functional recall responses. Interestingly, AMPKα1 deficiency abolishes the AMPKα1 but maintains the FOXO1 pathway and induces a metabolic switch from fatty acid oxidation to glycolysis in AMPKα1 KO IL-7/TM cells, leading to loss of cell survival and recall responses. Taken together, our data demonstrate that IL-7–stimulated weak strength of mTORC1–S6K signaling controls T cell memory via activation of transcriptional FOXO1–TCF1–Id3 and metabolic AMPKα1–ULK1–ATG7 pathways. This (to our knowledge) novel finding provides a new mechanism for a distinct IL-2/IL-7 stimulation model in T cell memory and greatly impacts vaccine development.