FOXO1 deficiency impairs proteostasis in aged T cells

Area of Science:

• Immunology
• Cell Biology
• Aging Research

Background:

• T cell differentiation involves dynamic FOXO1 expression, crucial for immune responses.
• FOXO1 reexpression is impaired in older individuals' CD4+ T cells, affecting immune function.
• Lysosome function is vital for cellular health and protein turnover.

Purpose of the Study:

• To investigate the role of FOXO1 in lysosome function and its impact on T cell aging.
• To elucidate the mechanisms by which impaired FOXO1 reexpression contributes to T cell senescence.

Main Methods:

• Analysis of FOXO1 expression dynamics in activated CD4+ T cells.
• Investigating FOXO1's role in TFEB induction and lysosome function.
• Assessing multivesicular body (MVB) expansion and GSK3β sequestration.
• Evaluating cellular features of senescence and exosome secretion.

Main Results:

• FOXO1 promotes lysosome function via TFEB induction.
• Reduced FOXO1 reexpression impairs lysosomal activity and causes MVB expansion.
• MVB expansion sequesters GSK3β, suppressing protein turnover and increasing glycolysis.
• Older T cells exhibit senescence features, including increased cell mass, effector differentiation, and harmful exosome release.

Conclusions:

• Impaired FOXO1 reexpression in aging CD4+ T cells disrupts lysosome function, promoting a senescence-like phenotype.
• This dysfunction leads to altered cellular metabolism and the secretion of cytotoxic exosomes.
• Findings highlight a novel mechanism linking aging, T cell dysfunction, and immune senescence.