Alcohol-sourced acetate impairs T cell function by promoting cortactin acetylation.

Area of Science:

• Immunology
• Cell Biology
• Biochemistry

Background:

• Alcohol is a widely consumed substance with known detrimental effects on organs like the liver, heart, and brain.
• Alcohol consumption significantly impacts the immune system, particularly T cell function.
• The precise molecular mechanisms by which alcohol affects T cells are not fully understood.

Purpose of the Study:

• To investigate how alcohol consumption impairs T cell function at a molecular level.
• To identify specific proteins and pathways involved in alcohol-induced T cell dysfunction.
• To explore potential therapeutic targets for mitigating alcohol's negative effects on immunity.

Main Methods:

• Analysis of acetate accumulation in lymphoid organs following alcohol consumption.
• Investigating the effect of acetate on cortactin acetylation in T cells.
• Utilizing in vitro and in vivo models, including T cell assays and an influenza infection model in mice.
• Employing techniques such as cortactin knockout and mutated cortactin expression to assess functional impacts.

Main Results:

• Alcohol metabolite acetate accumulates in lymphoid organs and increases cortactin acetylation in T cells.
• Acetylated cortactin shows reduced filamentous actin binding, impairing T cell migration, immune synapse formation, and activation.
• Mutant acetylation-resistant cortactin partially rescues acetate-induced T cell migration defects.
• Acetate-induced cytoskeletal changes inhibit T cell activation, proliferation, and immune synapse formation both in vitro and in vivo.

Conclusions:

• Alcohol impairs T cell function through cortactin acetylation, affecting cytoskeletal dynamics.
• Cortactin is a key mediator of alcohol's detrimental effects on T cell immunity.
• Targeting cortactin acetylation may offer a strategy for treating T cell-mediated autoimmune diseases.