Professor/Investigator Feinstein Institutes for Medical Research, Northwell Health Manhasset, New York, United States
Disclosure(s):
Betsy J. Barnes, PhD: No financial relationships to disclose
Introduction/Rationale: T cell activation is a meticulously orchestrated process that demands changes in cellular physiology, encompassing extensive transcriptional, translational, and metabolic reprogramming. While these layers of cellular regulation are crucial for T cell differentiation and function, the precise regulatory mechanisms that functionally link them remain incompletely defined. We investigated if T cell-intrinsic IRF5 exerts control beyond transcription and integrates with metabolic pathways.
Methods: T cells from WT and Irf5-/- mice were activated in vitro (anti-CD3/CD28); activation (CD25, CD69, proliferation) was assessed by flow cytometry. CD40L mRNA and protein were measured. Metabolism was characterized via targeted metabolomics and nutrient transporter expression. Single-cell flow/scRNA-seq analyzed global T cell population shifts. In vivo, EAE models (Irf5-/-, T cell conditional Irf5-/-, adoptive transfer of MOG-specific Irf5-/- T cells) were used and EAE progression scored. Mechanistic analyses included mTORC1 activity, CD40L, glutamine transporters, and inflammatory cytokines in EAE mice.
Results: IRF5 is a novel T cell-intrinsic regulator of mTORC1 signaling and glutamine metabolism. Irf5 ablation impaired CD40L protein expression despite preserved mRNA induction. Loss of Irf5 shifted T cell metabolic programs and cellular bioenergetics. Single-cell analysis showed Irf5 deletion skewed T cell populations, altering differentiation. In vivo, conditional Irf5 deletion protected against EAE. Protection was due to suppressed mTORC1 activity, reduced CD40L, dysregulated glutamine transporter, and reduced inflammatory cytokines.
Conclusion: IRF5 integrates TCR signaling, metabolic reprogramming, and effector function. It regulates transcription and critical post-transcriptional events, influencing mTORC1 signaling, CD40L expression, and glutamine metabolism. Modulating IRF5 may offer a strategy to manipulate aberrant T cell responses and mitigate T cell-mediated autoimmune conditions.
