
==== Front
bioRxiv
BIORXIV
bioRxiv
2692-8205
Cold Spring Harbor Laboratory

10.1101/2024.08.26.609422
preprint
1
Article
IRF5 mediates adaptive immunity via altered glutamine metabolism, mTORC1 signaling and post-transcriptional regulation following T cell receptor activation
Brune Zarina
Lu Ailing
Moss Matthew
Brune Leianna
Huang Amanda
Matta Bharati
Barnes Betsy J
27 8 2024
2024.08.26.609422https://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
http://biorxiv.org/lookup/doi/10.1101/2024.08.26.609422
nihpp-2024.08.26.609422.pdf
ABSTRACT

Although dynamic alterations in transcriptional, translational, and metabolic programs have been described in T cells, the factors and pathways guiding these molecular shifts are poorly understood, with recent studies revealing a disassociation between transcriptional responses and protein expression following T cell receptor (TCR) stimulation. Previous studies identified interferon regulatory factor 5 (IRF5) in the transcriptional regulation of cytokines, chemotactic molecules and T effector transcription factors following TCR signaling. In this study, we identified T cell intrinsic IRF5 regulation of mTORC1 activity as a key modulator of CD40L protein expression. We further demonstrated a global shift in T cell metabolism, with alterations in glutamine metabolism accompanied by shifts in T cell populations at the single cell level due to loss of Irf5 . T cell conditional Irf5 knockout mice in a murine model of experimental autoimmune encephalomyelitis (EAE) demonstrated protection from clinical disease with conserved defects in mTORC1 activity and glutamine regulation. Together, these findings expand our mechanistic understanding of IRF5 as an intrinsic regulator of T effector function(s) and support the therapeutic targeting of IRF5 in multiple sclerosis.

Sentence Summary

Findings provide new insight into the mechanisms by which T cell intrinsic IRF5 regulates the adaptive immune response via modulation of mTORC1 signaling, glutamine metabolism, and protein translation.
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pmc
