AKT isoforms modulate Th1-like Treg generation and function in human autoimmune disease.

Area of Science:

• Immunology
• Cellular Biology
• Molecular Signaling

Background:

• Foxp3(+) regulatory T cells (Tregs) exhibit plasticity, influencing their function in various diseases.
• Acquisition of a T helper 1 (Th1) phenotype and IFNγ secretion by Tregs correlates with impaired suppressor function.
• The underlying molecular mechanisms for Th1-Treg generation and functional decline remain largely unknown.

Purpose of the Study:

• To elucidate the signaling pathways governing the generation of human Th1-Tregs.
• To investigate the role of the PI3K/AKT/Foxo1/3 cascade in IFNγ secretion by Tregs.
• To explore the therapeutic potential of targeting this pathway in autoimmune diseases, using multiple sclerosis (MS) as a model.

Main Methods:

• Genome-wide gene expression analysis and pathway analysis to identify key signaling cascades.
• Ex vivo studies to investigate the roles of AKT isoforms in Th1-Treg generation.
• In vivo studies using multiple sclerosis patients' Treg cells to assess pathway activation and therapeutic blockade.

Main Results:

• The PI3K/AKT/Foxo1/3 signaling cascade was identified as the primary pathway regulating IFNγ secretion in human Tregs.
• Opposing roles of different AKT isoforms in ex vivo Th1-Treg generation were described.
• The PI3K/AKT/Foxo1/3 pathway is activated in Tregs from untreated relapsing-remitting MS patients, and its blockade inhibits IFNγ secretion and restores Treg suppressive function.

Conclusions:

• The study defines a fundamental pathway regulating human Treg function and plasticity.
• Activation of the PI3K/AKT/Foxo1/3 pathway contributes to functional defects in Tregs observed in autoimmune diseases.
• Targeting the PI3K/AKT/Foxo1/3 pathway presents a novel therapeutic strategy for autoimmune disorders.