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Citrate Compartmentalization Controls Calcium-Dependent Cytokine Production in Effector T Cells.

Andrea L Cote, Claire L McIntyre, Joshua A Acklin

Biorxiv : the Preprint Server for Biology

|June 22, 2026

Summary

Effector T cells use citrate compartmentalization to control cytokine production based on glucose availability. This mechanism links glucose metabolism to calcium signaling, impacting immune responses and cancer cell biology.

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Imaging Initial Ca2+ Microdomains in Primary T Cells

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Published on: October 4, 2024

Area of Science:

Immunology
Cell Biology
Metabolic Regulation

Background:

Cytokine production by effector T cells is crucial for immune responses but poorly understood.
Mechanisms linking cellular metabolism to immune cell function require further elucidation.

Purpose of the Study:

To identify cellular mechanisms regulating T cell cytokine production in response to glucose availability.
To investigate the role of citrate metabolism in coupling glucose levels to calcium signaling pathways.

Main Methods:

Investigated citrate transport by SLC25A1 in CD8+ T cells.
Manipulated glucose availability and mitochondrial citrate exchange.
Assessed cytosolic calcium levels and NFAT transcription factor activity.
Analyzed metabolic signatures in human cancer cell lines and tumor tissues.

Main Results:

Citrate transport into the cytosol suppresses calcium signaling and cytokine production under high glucose.
Reduced glucose or blocked citrate transport increases cytosolic calcium, promoting T cell cytokine output.
Citrate acts as a calcium-chelating metabolite, linking mitochondrial metabolism to calcium-dependent signaling.
This regulatory mechanism is conserved in human cancer cells and tumors.

Conclusions:

Cytosolic citrate acts as a metabolic rheostat, coupling glucose availability to calcium signaling in T cells.
Mitochondria adaptively tune cytokine expression and calcium-dependent programs via citrate based on local metabolic conditions.
This finding expands the known functions of SLC25A1 to include calcium signaling regulation.