| First Author | Xu A | Year | 2022 |
| Journal | J Immunol | Volume | 208 |
| Issue | 1 | Pages | 155-168 |
| PubMed ID | 34872976 | Mgi Jnum | J:316316 |
| Mgi Id | MGI:6835676 | Doi | 10.4049/jimmunol.2100452 |
| Citation | Xu A, et al. (2021) Prosurvival IL-7-Stimulated Weak Strength of mTORC1-S6K Controls T Cell Memory via Transcriptional FOXO1-TCF1-Id3 and Metabolic AMPKalpha1-ULK1-ATG7 Pathways. J Immunol |
| abstractText | CD8(+) memory T (TM) cells play a critical role in immune defense against infection. Two common gamma-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 AMPKalpha1-knockout (KO)/OTI mice. By using genetic and pharmaceutical tools, we demonstrate that IL-7 deficiency represses expression of FOXO1, TCF1, p-AMPKalpha1 (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/S6K(strong) and IL-7/S6K(weak)) 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/S6K(weak)-stimulated TM (IL-7/TM) and the control IL-2/S6K(strong)-stimulated TE (IL-2/TE) cells. We determine that the IL-7/S6K(weak) signal activates transcriptional FOXO1, TCF1, and Id3 and metabolic p-AMPKalpha1, 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, AMPKalpha1 deficiency abolishes the AMPKalpha1 but maintains the FOXO1 pathway and induces a metabolic switch from fatty acid oxidation to glycolysis in AMPKalpha1 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 AMPKalpha1-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. |
