Choline in immunity: a key regulator of immune cell activation and function

Abstract

Nutrient availability is a strong determinant of cell function. Immune cells, which must rapidly activate transcriptional, proteomic, and metabolic programs to fulfill their functional roles, depend on nutrient supply to generate the building blocks needed for the production of immune effectors. While glucose, glutamine, and amino acids are well-recognized as critical energy sources and carbon donors during immune activation, the contribution of choline, a vitamin-like metabolite, has been overlooked. Once taken up by cells, choline plays a vital role in several biological processes. It is a precursor for phosphatidylcholine, the primary phospholipid in cellular membranes, and is also essential for synthesizing the neurotransmitter acetylcholine. Additionally, when directed toward mitochondria and betaine synthesis, choline serves as a methyl donor for histone and protein methylation, key processes that regulate gene expression and cellular activity. In this review, we examine the latest research on how immune cells utilize and metabolize choline, as well as its broader implications for immune-related disorders and overall human health. We also discuss recent and ongoing clinical studies investigating the effects of choline supplementation and the potential use of choline-derived metabolites as biomarkers for therapy response.

Keywords: acetylcholine (ACh); choline; choline kinase (ChoK); immune cells; immunity; inflammation; phosphatidylcholine (PC); phosphocholine.

Figure 1

Choline intake, distribution, and metabolism. Intake of choline-rich foods provides choline bound to lipids or as a free soluble metabolite for reabsorption by intestinal cells or poured into the circulation. Intestinal bacteria uptake choline to generate the metabolite trimethylamine (TMA) that through the portal vein reaches the liver to be converted into trimethylamine N-oxide (TMAO). Circulating and tissue-resident immune cells are exposed to choline-containing lipids, free-choline, TMA, and TMAO, and respond to changes in physiological levels. Created in BioRender. Sanchez Lopez, E. (2025) https://BioRender.com/cs12pz8.

Figure 2

Choline transporters and utilization. Choline is transported into the cells via high- (CHTS), intermediate- (CTLs), and low-affinity (OCTs) linked to distinct metabolic fates. Left panel: CTLs mediate the uptake of choline for PC production through the Kennedy pathway. Choline is phosphorylated by Choline kinase (ChoK) to form phosphocholine, then converted into CDP-choline by the CTP:phosphocholine cytidylyltransferase (CCT). CDP-choline is converted into PC, the main phospholipid in cellular membranes, by the choline/ethanolamine phosphotransferase (CEPT). CTLs also localize to the mitochondrial membrane where, along with SLC25A48, they mediate choline import into the mitochondria for the generation of betaine, a precursor of methionine and dimethylglycine (DMG), s-adenosylmethionine (SAM), s-adenosylhomocysteine (SAH), and homocysteine (Hcys), all key methylation intermediates for DNA and protein methylation. Middle panel: High-affinity CHTS supports choline uptake for acetylcholine (ACh) synthesis through the choline acetyltransferase (CHAT), a reaction that can be reversed by acetylcholine esterase (AChE), releasing choline and acetate. Acetylcholine acts on both nicotinic and muscarinic receptors to mediate cholinergic signaling. Right panel: Low-affinity organic cation transporters contribute to choline uptake for both ACh and PC synthesis. However, their role in mitochondrial choline utilization and methionine synthesis remains unknown. PPi, inorganic pyrophosphate; DAG, Diacylglycerol; AC, adenylyl cyclase; IP3, inositol 1,4,5-triphosphate. Created in BioRender. Sanchez Lopez, E. (2025). https://BioRender.com/ahp7xe9.

Figure 3

Central mechanisms of choline utilization and metabolism in the different immune cell types. Macrophage/Monocytes: Activation of macrophages (e.g., LPS, IFNy, Poly(I:C), IL-4) increases choline uptake via choline transporter-like protein 1 (CTL1) and PC synthesis. Impaired choline uptake or PCho production disrupts mitochondrial PC and SM, increasing mitophagy, restraining NLRP3 inflammasome activation and IL-1b and IL-18 production; and favors DAG accumulation and PKC activation; and suppresses IL-4-induced mitochondrial genes and Retina expression. Choline supplementation increased SLC4A7, CHDH, CHKA, and CHAT. Neutrophils: PMA and fMLP increase PC from the condensation reaction of choline and DAG formed from PC- derived phosphatidic acid. fMLP also increases PC dependent and independent of Choka activity. High choline diminishes neutrophils' phagocytic and killing capacities, reduces oxidative burst capacity, and decreases ROS production. NK cells: Human decidual NK (dNK) cells display a unique high saturated phospholipid profile compared to blood NK cells (decreased PC, LPC, PE, LPE, PG, LPI, and PS; increased PA, PG (16:0/0:0), PC(16:0/3:1 (2E)) and PI(16:0/16:0)), which difficult forming immune synapses. CD56dim PC- phospholipase C (PLC) bright NK cells are associated with cytotoxic function, whereas CD56brightPC-PLClow- cells exhibit immunoregulatory properties. B cells: Increased synthesis of PC supports rough endoplasmic reticulum (ER) expansion and upregulation of ER chaperones such as BIP and GRP94, immunoglobulin synthesis, and assembly. CCTa-deficient B cells show impaired class switching, reducing antigen-specific IgG1 production while increasing IgM secretion upon antigen challenge. T cells: Viral infection increases ChAT expression in CD4+ and CD8+ T cells in an IL21-dependent manner and via PI3K signaling cascade activation and the Th2-associated master regulator GATA3. T-cell-derived ACh boosts endothelial nitric oxide synthase (eNOS) activity and vasorelaxation and reduces inflammation. Created in BioRender. Sanchez Lopez, E. (2025). https://BioRender.com/6mvmfzs.