CARMIL2 Deficiency Disrupts Activation-Induced Metabolic Reprogramming in T Cells and is Partially Rescued by Glutamine Supplementation

עמוד ראשי > מאמרים > CARMIL2 Deficiency Disrupts Activation-Induced Metabolic Reprogramming in T Cells and is Partially Rescued by Glutamine Supplementation

CARMIL2 Deficiency Disrupts Activation-Induced Metabolic Reprogramming in T Cells and is Partially Rescued by Glutamine Supplementation

Mona Kabha, PhD, *Maya Liaks-Bohnick, MS * Fadia Zagairy, PhD,Orna Atar, PhD,Mira Hamed, MD,cMichael Ziv, MD,Nada Danial-Farran, PhD,Morad Khayat, PhD, Orly Ishach, MD,e Yael Dinur-Schejter, MD,f Vered Molho-Pessach, MD,g Ido Somekh, MD,h Shirly Frizinsky, MD,h Efrat Bar-Ilan, MD,i Shoshana Greenberger, MD, PhD,i NaserEddin Adeeb, MD,f Raz Somech, MD, PhD, Polina Stepansky, MD,Noga Ron-Harel, PhD, and Eran Cohen-Barak, MD

23/11/2025

Background: T-cell activation requires signaling through the T-cell receptor and costimulatory molecules, including CD28, triggering metabolic reprogramming to support growth and proliferation of the activating T cell. CARMIL2, a scaffold protein, facilitates CD28-mediated signaling. Individuals with CARMIL2 mutations experience inborn errors of immunity, leading to T-cell dysfunction and severe infectious and inflammatory comorbidities. However, how CARMIL2 deficiency impacts T-cell metabolic reprogramming remains unknown.

Objective: We sought to investigate how CARMIL2 deficiency affects activation-induced metabolic reprogramming in T cells.

Methods: CD4+ T cells were isolated from patients with CARMIL2 deficiency and matched healthy controls. A transcriptomic profile was analyzed by bulk RNA sequencing and whole-cell metabolomics by LC-MS/MS. Activation markers and signaling pathways were measured by flow cytometry. These approaches informed identification of specific amino acids for rescue experiments.

Results: Nine patients with CARMIL2 deficiency and 16 ageand sex-matched healthy controls were recruited. RNA sequencing of CD4+ T cells revealed decreased expression of genes associated with metabolic activity, including mTOR signaling, glycolysis, 1-carbon metabolism, and glutamine metabolism. Whole-cell metabolomics reinforced these results and highlighted glutamine deficiency as a potential driver of the observed metabolic phenotype. Glutamine supplementation restored NF-𝛋B and mTOR activity, as measured by p-65 and RPS6 phosphorylation, respectively, and upregulated the expression of IL17A in CARMIL2-mutated CD4+ T cells.

Conclusion: CARMIL2 deficiency disrupts T-cell metabolic reprogramming and was partially rescued ex vivo with glutamine supplementation. These findings highlight a potential therapeutic approach targeting metabolism to improve immune function in individuals with CARMIL2 deficiency. (J Allergy Clin Immunol 2025;156:1390-400.)

Read the Full Text