ACLY and ACSS2 link nutrient-dependent chromatin accessibility to CD8 T cell effector responses

Area of Science:

• Immunology
• Cellular Metabolism
• Epigenetics

Background:

• Cellular metabolism coordination is crucial for effective T cell responses.
• Cytosolic acetyl-CoA is a key metabolic intermediate impacting cellular functions.

Purpose of the Study:

• To identify critical metabolic pathways for CD8 T cell function in vivo.
• To elucidate the roles of ATP citrate lyase (ACLY) and acyl-CoA synthetase short-chain family member 2 (ACSS2) in CD8 T cell metabolism.

Main Methods:

• Investigated CD8 T cell responses to infection in vivo.
• Utilized genetic ablation of ACLY to study alternative metabolic pathways.
• Analyzed the impact of acetate metabolism on T cell effector functions and histone acetylation.

Main Results:

• CD8 T cell responses to infection rely on acetyl-CoA produced by ACLY.
• Loss of ACLY activates an alternative, acetate-dependent pathway via ACSS2 for acetyl-CoA production.
• Acetate fuels the TCA cycle and cytosolic acetyl-CoA, influencing T cell effector responses and chromatin accessibility.

Conclusions:

• ACLY and ACSS2 are key regulators of cytosolic acetyl-CoA production in CD8 T cells.
• This metabolic coordination is essential for maintaining chromatin accessibility and T cell effector function.
• While not obligate, acetate metabolism via ACSS2 becomes critical when ACLY is non-functional.