Tryptophan degradation by human placental indoleamine 2,3-dioxygenase regulates lymphocyte proliferation

1. The physiological importance of human placental indoleamine 2,3-dioxygen ase (EC 1.13.11.42), the first and rate-limiting enzyme in tryptophan metab olism, in regulating feto-maternal immunology has been studied. 2. Concentrations were measured in placental villous explant conditioned me dia of 14 amino acids that are known to be required for lymphocyte prolifer ation, In the absence of interferon-gamma only tryptophan and threonine wer e significantly lowered; in the presence of interferon-gamma (known to stim ulate indoleamine 2,3-dioxyenase) tryptophan but not threonine depletion wa s much greater. 3. Peripheral blood mononuclear cell proliferation determined by measuring thymidine incorporation into DNA following culture in the medium previously conditioned by culture of villous explants was markedly reduced when place ntal indoleamine 2,3-dioxygenase was stimulated with interferon-gamma. Inhi bition of placental indoleamine 2,3-dioxygenase by 1-methyl- tryptophan pre vented inhibition of thymidine incorporation. Supplementation of the condit ioned tuedium with tryptophan but no other amino acid completely reversed t he inhibition of thymidine incorporation. 4. Flow cytometric analysis showed that CD4-positive T lymphocyte division was specifically suppressed by indoleamine 2,3 -dioxygenase-mediated trypto phan depletion. This inhibition of T cell proliferation was clue to arrest of cell cycle progression. 5. To study the mechanism of tryptophan sensing we examined the ability of 11 L-tryptophan analogues to support lymphocyte proliferation. Only L-trypt ophan methyl and ethyl esters were able to stimulate proliferation in trypt ophan-free media. Since both of these molecules are readily degraded to try ptophan by intracellular esterases this suggests that the tryptophan sensor is intracellular. 6. Our results show that mechanisms are present in the human placenta which are able to regulate cellular proliferation of the maternal immune system. This mechanism is dependent both on placental indoleamine, 2,3-dioxygenase -mediated tryptophan degradation and on tryptophan sensing systems within l ymphocytes.