Dietary arginine drives codon-dependent MHC class I translation and improves immunity in colon tumorigenesis and respiratory viral infection.

Summary

This study identifies an unrecognized nutrient-to-translation pathway in which extracellular arginine availability regulates specific arginine tRNAs and codon-dependent translation of MHC class I. In mouse models, arginine restriction impaired immunity to influenza and SARS-CoV-2 and promoted colon tumorigenesis, whereas dietary supplementation or myeloid-specific arginase 1 deletion improved antigen presentation and disease outcomes.

Key Findings

• Extracellular arginine restriction suppressed specific arginine tRNAs and reduced codon-dependent MHC class I translation and antigen presentation.
• Dietary arginine restriction impaired antiviral immunity to influenza and SARS-CoV-2 and increased colon tumorigenesis in mice.
• Arginine supplementation or myeloid-specific arginase 1 deletion increased MHC class I expression, reduced tumorigenesis, and improved respiratory viral outcomes; these effects required β2-microglobulin.

Clinical Implications

Arginine status may eventually become a modifiable determinant of antiviral vaccine or infection responses, particularly in malnutrition, cancer, or severe infection. Clinical supplementation should not yet be adopted solely on the basis of these preclinical findings; dose, timing, patient selection, and oncologic safety require prospective human studies.

Limitations

• The evidence is predominantly preclinical and was generated in mouse models rather than human clinical cohorts.
• The safety, optimal dose, timing, and disease-specific effects of arginine supplementation remain unresolved, particularly in cancer and severe infection.

Future Directions

Human studies should determine whether plasma or tissue arginine availability predicts antigen-presentation capacity and antiviral outcomes. Future trials should evaluate biomarker-guided supplementation while monitoring viral control, inflammatory toxicity, tumor growth, and interactions with immunotherapy.