The eIF4EBP-eIF4E axis regulates CD4+ T cell differentiation through modulation of T cell activation and metabolism
Roman Istomine,
Tho-Alfakar Al-Aubodah,
Fernando Alvarez,
Jacob A. Smith,
Carston Wagner,
Ciriaco A. Piccirillo
Affiliations
Roman Istomine
Department of Microbiology and Immunology, McGill University, Montréal, QC H3A 2B4, Canada; Program in Infectious Diseases and Immunology in Global Health, Centre for Translational Biology, Research Institute of the McGill University Health Centre, Montréal, QC H4A 3J1, Canada; Centre of Excellence in Translational Immunology (CETI), Montréal, QC H4A 3J1, Canada
Tho-Alfakar Al-Aubodah
Department of Microbiology and Immunology, McGill University, Montréal, QC H3A 2B4, Canada; Program in Infectious Diseases and Immunology in Global Health, Centre for Translational Biology, Research Institute of the McGill University Health Centre, Montréal, QC H4A 3J1, Canada; Centre of Excellence in Translational Immunology (CETI), Montréal, QC H4A 3J1, Canada
Fernando Alvarez
Department of Microbiology and Immunology, McGill University, Montréal, QC H3A 2B4, Canada; Program in Infectious Diseases and Immunology in Global Health, Centre for Translational Biology, Research Institute of the McGill University Health Centre, Montréal, QC H4A 3J1, Canada; Centre of Excellence in Translational Immunology (CETI), Montréal, QC H4A 3J1, Canada
Jacob A. Smith
Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, USA
Carston Wagner
Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, USA
Ciriaco A. Piccirillo
Department of Microbiology and Immunology, McGill University, Montréal, QC H3A 2B4, Canada; Program in Infectious Diseases and Immunology in Global Health, Centre for Translational Biology, Research Institute of the McGill University Health Centre, Montréal, QC H4A 3J1, Canada; Centre of Excellence in Translational Immunology (CETI), Montréal, QC H4A 3J1, Canada; Corresponding author
Summary: CD4+ T cells are critical for adaptive immunity, differentiating into distinct effector and regulatory subsets. Although the transcriptional programs underlying their differentiation are known, recent research has highlighted the importance of mRNA translation in determining protein abundance. We previously conducted genome-wide analysis of translation in CD4+ T cells revealing distinct translational signatures distinguishing these subsets, identifying eIF4E as a central differentially translated transcript. As eIF4E is vital for eukaryotic translation, we examined how altered eIF4E activity affected T cell function using mice lacking eIF4E-binding proteins (BP-/-). BP-/- effector T cells showed elevated Th1 responses ex vivo and upon viral challenge with enhanced Th1 differentiation observed in vitro. This was accompanied by increased TCR activation and elevated glycolytic activity. This study highlights how regulating T cell-intrinsic eIF4E activity can influence T cell activation and differentiation, suggesting the eIF4EBP-eIF4E axis as a potential therapeutic target for controlling aberrant T cell responses.
