Pro-survival IL-7-stimulated weak strength of mTORC1-S6K signaling controls T cell memory via transcriptional FOXO1 and metabolic AMPK pathways

Abstract

Abstract Distinct strengths of stimuli (DSS) is a well-known model for T cell memory. Two common γ-chain (γc)-family cytokines IL-2 and IL-7, which trigger the same mTORC1-S6K pathway, distinctly induce effector T (Te) cells and memory T (Tm) cell differentiation. However, their underlying mechanisms are elusive. In this study, we want to elucidate molecular mechanism for IL-7-induced Tm (IL-7/Tm) cells by performing in vitro and in vivo experiments using genetic and pharmacological tools. We show that IL-2 and IL-7 stimulate strong and weak S6K signals leading to IL-7R−CD62L−KLRG1+ Te and IL-7R+CD62L+KLRG1− Tm cell formation in our study model of adoptive transfer of T cells derived from wild-type and IL-7R knockout (KO)/OTI mice and L. monocytogenes rLmOVA infection. We further show that IL-7/Tm cells upregulate transcriptional factors (FOXO1, Id3 and TCF1) for regulating Tm’s differentiation and promote expression of autophagy/metabolic molecules (AMPK, ULK1 and ATG7) for controlling Tm’s fatty acid oxidation (FAO) metabolism by flow cytometry, Western blotting, confocal and electron microscopy and Seahorse assay analyses, and vice versa for IL-2-induced Te (IL-2/Te) cells. IL-7/Tm cells derived from AMPK KO/OTI mice abolish expression of ULK1 and ATG7, FAO metabolism and long-term survival, while IL-2/Te cells with S6K deficiency show Tm’s differentiation, metabolic/transcriptional pathways and prolonged survival. Taken together, our data demonstrate that pro-survival IL-7-stimulated weak S6K signaling controls T cell memory via transcriptional FOXO1 and metabolic AMPK pathways. The novel finding provides a new potential mechanism for DSS model in T cell memory and has a great impact on vaccine development and immunotherapy.