The requirement of dietary nucleotide sources for maximal helper T-cell function has been demonstrated. The effect of dietary nucleotide restriction was tested during two forms of nutritional stress: starvation and protein malnutrition. In the starvation model, mice were fed chow diet, nucleotide free or nucleotide free supplemented with 0.25% yeast RNA, for at least 4 weeks. The animals were then starved for 5 days, at which time they were killed and mitogen assays were performed using spleen cells. Animals previously maintained on the nucleotide-free diet supplemented with RNA showed a significant increase in spontaneous concanavalin A and phytohemagglutinin-stimulated blastogenesis. Protein malnutrition was induced by feeding Balb/c mice a protein-free diet for 7 to 10 days. These mice then received either the protein-free diet, the nucleotide-free diet, or the nucleotide-free diet supplemented with 0.25% yeast RNA. Popliteal lymph node assays were then performed. The chow diet, nucleotide-free diet, and nucleotide-free diet supplemented with 0.25% yeast RNA led to a restoration of body weight, but only the chow and supplemented diets restored significant popliteal lymph node immune reactivity. These studies using starvation and protein-malnutrition models clearly indicate the nutritional role of nucleotides in the maintenance and restoration of the immune response.