An observed phenomenon of cell mediated immunosuppression in mice caused by the lack of preformed purine and pyrimidines in the diet was characterized and the mechanism of action explored utilizing three different approaches. The three approaches employed were as follows: (1) measurement of T cell mediated immune response in vitro and in vivo; (2) analysis of lymphocyte phenotype involving surface marker immunofluorescence, measurement of the levels of purine and pyrimidine enzymes as predictors of lymphocyte maturation and evaluation of putative G\sb1 phase characteristics; and (3) examination of diet fed host effects on the in vivo out growth of syngeneic lymphoid tumors. Balb/c mice fed a nucleotide free (NF) diet exhibited significantly decreased T helper/inducer cell function and number relative to mice fed normal rodent chow (F) or NF plus RNA (NFR). Lymphoproliferative response in vitro and in vivo was significantly lower in mice fed the NF diet than the response exhibited by mice fed the control diets or NF plus uracil (NFU). This lack of proliferative response was accompanied by decreased induction of two purine enzymes important to the immune response: adenosine deaminase and purine nucleoside phosphorylase. Bone marrow, thymus and spleen obtained from NF diet fed mice contained significantly more T cells of an immature phenotype with high terminal deoxynucleotidyl transferase and adenosine deaminase levels and low purine nucleoside phosphorylase level enzyme profiles relative to that of similar lymphoid tissues obtained from mice fed the control diets. Levels of ecto 5\sp′ nucleotidase, another enzyme linked to optimal B cell function were not affected by the NF diet. Lymphocyte nucleotide pools were altered and the number of putative G\sb1 phase T lymphocytes were increased in mice fed the NF diet relative to mice fed the purine and pyrimidine supplemented diets. In vivo outgrowth of the syngeneic T cell lymphoma, 5F4, in Balb/c hosts fed the NF diet was significantly decreased compared to the 5F4 tumor growth observed in mice fed the NF diet supplemented with RNA, adenine or uracil. (Abstract shortened with permission of author.)