Tryptophan-derived Catabolites Are Responsible for Inhibition of T and Natural Killer Cell Proliferation Induced by Indoleamine 2,3-Dioxygenase

TLDR

Macrophages stimulated with macrophage colony‑stimulating factor suppress T‑cell proliferation through de novo expression of indoleamine 2,3‑dioxygenase (IDO). The study investigates whether IDO suppresses cell proliferation by generating catabolites and depleting extracellular tryptophan. IDO was purified and its activity tested in vitro on activated T cells and NK cells, and the effects of tryptophan and its catabolites were examined. IDO inhibited proliferation of CD4⁺, CD8⁺ T cells and NK cells but not B cells; l‑kynurenine and picolinic acid suppressed activated cells even at lower concentrations when tryptophan was absent, quinolinic acid gained inhibitory activity, and resting cells were unaffected.

Abstract

Macrophages exposed to macrophage colony-stimulating factor acquire the capacity to suppress T cell proliferation; this effect is associated with de novo expression of the tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase (IDO). We have purified IDO and tested its activity in in vitro models of T cell activation. IDO was able to inhibit proliferation of CD4+ T lymphocytes, CD8+ T lymphocytes, and natural killer (NK) cells; proliferation of B lymphocytes was not affected. The inhibitory role of tryptophan and of its catabolites was then tested. In the presence of tryptophan, only l-kynurenine and picolinic acid inhibit cell proliferation. In a tryptophan-free medium cell proliferation was not affected. In the absence of tryptophan inhibition induced by l-kynurenine and picolinic acid was observed at concentrations below the lowest concentration that was effective in the presence of tryptophan, and quinolinic acid acquired some inhibitory capacity. Inhibition of cell proliferation induced by the tryptophan catabolites resulting from IDO activity was selective, applying only to cells undergoing activation. Resting cells were not affected and could subsequently activate normally. We suggest that IDO exerts its effect on cell proliferation by (i) starting the cascade of biochemical reactions that produce the three catabolites and by (ii) enhancing their inhibitory potential by depriving the extracellular microenvironment of tryptophan.