HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

Published online before print September 22, 2006

This Article Full Text (Reprint (PDF)) All Versions of this Article: jlb.1205727v1 80/6/1320    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Seymour, R. L. Articles by Munn, D. H. Search for Related Content PubMed PubMed Citation Articles by Seymour, R. L. Articles by Munn, D. H.

© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.1205727

Received for publication December 9, 2005.
Revised August 12, 2006.
Accepted for publication August 16, 2006.

Article

A high-affinity, tryptophan-selective amino acid transport system in human macrophages

Robert L. Seymour ^*, Vadivel Ganapathy , Andrew L. Mellor ^*, and David H. Munn ^*@

*Immunotherapy Center and Departments of Biochemistry and Molecular Biology, Medicine, and Pediatrics, Medical College of Georgia, Augusta

^@ To whom correspondence should be addressed. E-mail: dmunn{at}mail.mcg.edu.

	Abstract

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, and 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.

Key Words: indoleamine 2,3-dioxygenase • antigen-presenting cells • tolerance

This article has been cited by other articles:

				R. M. Leonhardt, S.-J. Lee, P. B. Kavathas, and P. Cresswell Severe Tryptophan Starvation Blocks Onset of Conventional Persistence and Reduces Reactivation of Chlamydia trachomatis Infect. Immun., November 1, 2007; 75(11): 5105 - 5117. [Abstract] [Full Text] [PDF]

				M. C. Cuffy, A. M. Silverio, L. Qin, Y. Wang, R. Eid, G. Brandacher, F. G. Lakkis, D. Fuchs, J. S. Pober, and G. Tellides Induction of Indoleamine 2,3-Dioxygenase in Vascular Smooth Muscle Cells by Interferon-{gamma} Contributes to Medial Immunoprivilege J. Immunol., October 15, 2007; 179(8): 5246 - 5254. [Abstract] [Full Text] [PDF]