A high-affinity, tryptophan-selective amino acid transport system in human macrophages.
Tryptophan catabolism via the enzyme indoleamine 2,3-dioxygenase (IDO) allows human monocyte-derived macrophages (MDM) and other APC to suppress T cell proliferation. IDO helps protect murine fetuses from rejection by the maternal immune system and can promote tolerance and immunosuppression. For tryptophan to be catabolized by IDO, it must first enter the APC via transmembrane transport. It has been shown that MDM in vitro readily deplete tryptophan present in the extracellular medium to nanomolar levels via IDO activity; yet, no currently known amino acid transport system displays high affinity and specificity sufficiently to permit efficient uptake of tryptophan at these low concentrations. Here, we provide biochemical characterization of a novel transport system with nanomolar affinity and high selectivity for tryptophan. Tryptophan transport in MDM was predominantly sodium-independent and occurred via two distinct systems: one consistent with the known system L transporter and a second system with 100-fold higher affinity for tryptophan (Km<300 nM). Competition studies showed that the high-affinity system did not correspond to any known transporter activity and displayed a marked selectivity for tryptophan over other amino acids and tryptophan analogs. This new system was expressed at low levels in fresh monocytes but underwent selective induction during MDM differentiation. In contrast, resting human T cells expressed only the conventional system L. We speculate that the high-affinity, tryptophan-specific transport system allows MDM to take up tryptophan efficiently under conditions of low substrate concentration, such as may occur during interaction between T cells and IDO-expressing APC.
Seymour
Robert L
RL
Immunotherapy Center, CN-4141, Medical College of Georgia, Augusta, GA 30912, USA.
Ganapathy
Vadivel
V
Mellor
Andrew L
AL
Munn
David H
DH
D027062:Amino Acid Transport System L / Q000276:immunology*; D000818:Animals; D001693:Biological Transport, Active / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D002460:Cell Line; D049109:Cell Proliferation; D018920:Coculture Techniques; D005260:Female; D005333:Fetus / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000276:immunology* / Q000378:metabolism; D008264:Macrophages / Q000201:enzymology / Q000276:immunology*; D051379:Mice; D011247:Pregnancy / Q000276:immunology; D013601:T-Lymphocytes; D014364:Tryptophan / Q000276:immunology* / Q000378:metabolism
D027062:Amino Acid Transport System L; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D014364:Tryptophan