ATF4-SLC7A11-GSH axis mediates the acquisition of immunosuppressive properties by activated CD4+ T cells in low arginine condition

• Published in: Cell reports (Cambridge) 2024-04, Vol.43 (4), p.113995-113995, Article 113995
• Main Authors: Zou, Ziqi, Cheng, Qian, Zhou, Jiajie, Guo, Chenyao, Hadjinicolaou, Andreas V., Salio, Mariolina, Liang, Xinghua, Yang, Cuiyu, Du, Yue, Yao, Weiran, Wang, Dongrui, Cerundolo, Vincenzo, Wang, Qingqing, Xia, Meng
• Format: Article
• Language: English
• Subjects: Activating Transcription Factor 4 - metabolism; Amino Acid Transport System y+ - genetics; Amino Acid Transport System y+ - metabolism; Amino Acid Transport Systems, Basic - genetics; Amino Acid Transport Systems, Basic - metabolism; Animals; arginine; Arginine - metabolism; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; CP: Immunology; Female; Humans; immunosuppression; Lymphocyte Activation - immunology; Mice; Mice, Inbred C57BL; SLC7A11; T cells; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; tumor microenvironment; Tumor Microenvironment - immunology
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.113995

The tumor microenvironment (TME) is restricted in metabolic nutrients including the semi-essential amino acid arginine. While complete arginine deprivation causes T cell dysfunction, it remains unclear how arginine levels fluctuate in the TME to shape T cell fates. Here, we find that the 20-μM low arginine condition, representing the levels found in the plasma of patients with cancers, confers Treg-like immunosuppressive capacities upon activated T cells. In vivo mouse tumor models and human single-cell RNA-sequencing datasets reveal positive correlations between low arginine condition and intratumoral Treg accumulation. Mechanistically, low arginine-activated T cells engage in metabolic and transcriptional reprogramming, using the ATF4-SLC7A11-GSH axis, to preserve their suppressive function. These findings improve our understanding of the role of arginine in human T cell biology with potential applications for immunotherapy strategies. [Display omitted] •Low arginine condition confers upon activated CD4+ T cells Treg-like properties•Arginine starvation shapes T cell-associated intratumoral immune landscape•The immunosuppression of low arginine educated T cells rely on oxidative metabolism•Low arginine educated T cells keep immunosuppression via ATF4-SLC7A11-GSH axis Arginine availability shapes T cell fate. Xia and colleagues show that low arginine condition, as present in tumor microenvironments, confers Treg-like immunosuppressive properties upon activated CD4+ T cells via metabolic and transcriptional reprogramming, including keeping active oxidative metabolism and using ATF4-SLC7A11-GSH axis to get rid of the by-product ROS.