Autophagy-regulated mitochondrial inheritance controls early CD8⁺ T cell fate commitment

Area of Science:

• Immunology
• Cell Biology
• Aging Research

Background:

• T cell immunity declines with age.
• This decline is linked to reduced autophagy and asymmetric cell division.
• Mitochondrial quality control is crucial for T cell function.

Purpose of the Study:

• To investigate the role of autophagy in mitochondrial inheritance in CD8+ T cells.
• To understand how mitochondrial inheritance impacts T cell fate and function.
• To explore the metabolic consequences of asymmetric mitochondrial division.

Main Methods:

• Utilized a mouse model for sequential mitochondrial tagging in mother and daughter cells.
• Compared autophagy-deficient and autophagy-competent CD8+ T cells.
• Performed multiomics analyses to assess metabolic programs.

Main Results:

• Autophagy-deficient T cells showed symmetric inheritance of old mitochondria.
• Autophagy-competent cells exhibited asymmetric mitochondrial partitioning.
• Daughter cells retaining old mitochondria had reduced memory potential.
• Daughter cells with high mitochondrial turnover were long-lived and expanded upon antigen challenge.
• One-carbon metabolism was activated in cells retaining premitotic mitochondria.

Conclusions:

• Autophagy is essential for regulating mitochondrial inheritance and T cell fate.
• Asymmetric mitochondrial division establishes distinct daughter cell populations with differential function.
• Metabolic reprogramming, including one-carbon metabolism, drives early T cell fate divergence.
• Findings provide insights into T cell diversity and potential strategies for immune modulation.