Timely induction and subsequent contraction of interferon-gamma (IFN-γ)-producing CD4+ T cells is critical for infection clearance and re-establishing homeostasis, respectively 1. Insufficient downregulation of IFN-γ signaling and delayed induction of interleukin-10 (IL-10) by Th1 cells can lead to persistent normal tissue injury, as observed in cases of severe COVID-19 2. Understanding the factors that regulate these processes and their temporal dynamics is important for effective disease control. Amino acid metabolism, a well-documented regulator of immune responses in cancer, autoimmunity and inflammatory conditions 3, is associated with Th1 immune responses. Amino acid–dependent pathways, including L-arginine metabolism, shape T-cell differentiation and promote Th1 responses. Moreover, coordinated crosstalk between L-arginine metabolism, vitamin D signaling, and cholesterol biosynthesis can drive complement activation and induce IFN-γ–producing CD4+ T cells during infection 2, 4, 5. Arginase 1 (Arg1), the cytosolic isoform of the Arginase enzyme that converts L-arginine into ornithine and urea, can be induced by Th2 cytokines in alternatively-activated macrophages and linked to tumor-associated immunosuppression 6. However, its expression in T cells and in T cell responses to infection has been controversial. West et al. 7 identified Arg1 as one of the most highly-induced genes following influenza infection. T cell-specific conditional knockout (CKO) of Arg1 in a murine model of influenza demonstrated expedited induction of actively proliferating CD4+ T cells in the lungs and subsequent resolution of virus-specific Th1 responses compared to WT mice (Figure 1) 7. The role of Arg1 in regulating CD4+ T cell response kinetics appeared independent of Arg1 and its mitochondrial isoform Arg2 in CD8+ T cells 7. Arg1 CKO in CD4+ T cells also resulted in reduced glutaminolysis leading to altered IFN-γ and IL-10 production, an effect which was not observed following Arg1 CKO in CD8+ T cells. Arg1 expression therefore limits initial CD4+ T cell clonal proliferation following viral infection and delays transition to the IL-10–producing contraction phase in mice and humans. Arg1 is thus shown as a key metabolic checkpoint and therapeutic target in T cells that fine-tunes immune responses and limits tissue pathology in viral infections. Arg1-dependent regulation to CD4+ T cells, without Arg2 involvement and with different outcomes in CD8+ T cells, may stem from distinct metabolic demands or compartmentalised arginine use in the cytosol versus mitochondria. Such divergence suggests lineage-specific arginine flux, with CD4+ T cells relying on cytosolic Arg1, whereas CD8+ T cells use alternative mitochondrial pathways that circumvent Arg1 restriction. Exploring the molecular underpinnings of metabolic regulation of Th1 responses to infections could yield insights into immune dysregulation in cancer, allergy and inflammatory conditions (Figure 1). Altered glutamine metabolism is a hallmark of cancer, and glutamine blockade is linked to improved anti-tumor immunity 8. Arg1 in tumors is expressed by immunomodulatory myeloid cells 6. It shapes nutrient flux through regulation of L-arginine metabolism, indirectly affecting polyamine synthesis and T cell fitness under nutrient-deprived conditions which are typical of tumors 6. Within the immunosuppressive tumour microenvironment, Arg1 expression in CD4+ T cells may limit clonal expansion and prolonged inflammatory cytokine production, restricting anti-tumor immunity. Furthermore, Arg1 may influence the balance between pro-inflammatory and regulatory CD4+ T cell states, impacting chronic inflammation and tumour tolerance. Clarifying how Arg1 is regulated in human CD4+ T cells across cancer, infection, and allergic disease is essential for assessing its therapeutic potential. Human and mouse T cells may use distinct regulatory and metabolic pathways, altering Arg1 induction and its impact on effector function or Th1/Th2 balance. Species differences underscore this need; for example, murine red cell Arg1 activity is far lower than in humans 9, highlighting the importance of validating Arg1-targeted strategies directly in human immune cells. If Arg1 expression and functions in cancer-associated T cells are explored and elucidated, Arg1-directed treatments could potentially enhance CD4+ T cell effector function while diminishing Arg1-expressing myeloid cell-associated immunosuppression. This may open translational opportunities including targeted CAR T-cell therapies exploiting Arg1-specific immune responses in prolonged inflammation following infections. Given the diverse and cell type-dependent roles of Arg1, implementing cell type-specific interventions 5, 10. Furthermore, if induction of Arg1 by Th2 cytokines in CD4+ T cells can be confirmed, it would be valuable to elucidate whether this enzyme also regulates Th1 dynamics. Modulating this pathway could influence the Th1/Th2 balance, with potential implications for allergic sensitization and therapy across different immunological diseases. The authors have nothing to report. Anishaa Balaji reports grants from Apollo Therapeutics. Sophia N. Karagiannnis reports grants from Breast Cancer Now, Worldwide Cancer Research, and King's Health Partners Centre for Translational Medicine during the conduct of the study as well as grants and other support from Epsilogen Ltd. and grants from Apollo Therapeutics, Cancer Research UK, the Wellbeing of Women, The Medical Research Council, The Biotechnology and Biological Sciences Research Council, Cancer Research UK City of London Centre, British Skin Foundation, and the National Institute for Health Research outside the submitted work, is academic founder and shareholder of Epsilogen Ltd. and has authored patents on antibody technologies for cancer. Alexandra J. McCraw reports grants from Worldwide Cancer Research during the conduct of the study. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.
Balaji et al. (Thu,) studied this question.