CARMIL2 deficiency disrupts activation-induced metabolic reprogramming in T cells and is partially rescued by glutamine supplementation
Mona Kabha, Maya Liaks-Bohnick, Fadia Zagairy, Orna Atar, Mira Hamed, Michael Ziv, Nada Danial‐Farran, Morad Khayat, Orly Ishach, Yael Dinur-Schejter, Vered Molho‐Pessach, Ido Somekh, Shirly Frizinsky, Efrat Bar‐Ilan, Shoshana Greenberger, N Adeeb, Raz Somech, Polina Stepansky, Noga Ron‐Harel, Eran Cohen‐Barak
Abstract
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: 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: 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.