Am J Clin Exp Immunol 2012;1(2):113-123

Original Article
The cystine/glutamate antiporter regulates indoleamine 2,3-dioxygenase
protein levels and enzymatic activity in human dendritic cells

Mildred L Mattox, June A D’Angelo, Zachary M Grimes, Edda Fiebiger, Bonny L Dickinson

The West Virginia School of Osteopathic Medicine, 400 North Lee Street, Lewisburg, WV 24901; The Research
Institute for Children, Children’s Hospital and Department of Pediatrics, Louisiana State University Health Science
Center, New Orleans, LA 70118; Division of Gastroenterology and Nutrition, Children’s Hospital Boston, Harvard
Medical School, Boston, MA 02115

Received August 18, 2012; Accepted September 10, 2012; Epub September 27, 2012; Published November 30, 2012

Abstract: Indoleamine 2,3-dioxygenase (IDO) is the rate-limiting enzyme in the tryptophan-catabolizing pathway and
a key regulator of peripheral immune tolerance. As the suppressive effects of IDO are predominantly mediated by
dendritic cells (DCs) and IDO-competent DCs promote long-term immunologic tolerance, a detailed understanding
of how IDO expression and activity is regulated in these cells is central to the rational design of therapies to induce
robust immune tolerance. We previously reported that the cystine/glutamate antiporter modulates the functional
expression of IDO in human monocyte-derived DCs. Specifically, we showed that blocking antiporter uptake of cystine
significantly increased both IDO mRNA and IDO enzymatic activity and that this correlated with impaired DC
presentation of exogenous antigen to T cells via MHC class II and the cross-presentation pathway. The antiporter
regulates intracellular and extracellular redox by transporting cystine into the cell in exchange for glutamate. Intracellular
cystine is reduced to cysteine to support biosynthesis of the major cellular antioxidant glutathione and
cysteine is exported from the cell where it functions as an extracellular antioxidant. Here we show that antiporter
control of IDO expression in DCs is reversible, independent of interferon-γ, regulated by redox, and requires active
protein synthesis. These findings highlight a role for antiporter regulation of cellular redox as a critical control point
for modulating IDO expression and activity in DCs. Thus, systemic disease and aging, processes that perturb redox
homeostasis, may adversely affect immunity by promoting the generation of IDO-competent DCs. (AJCEI1208002).

Keywords: Indoleamine 2,3-dioxygenase, human monocyte-derived dendritic cells, tryptophan, kynurenine, cystine/
glutamate antiporter, glutathione, cystine, cysteine, peripheral immune tolerance, redox


Address all correspondence to:
Dr. Bonny L Dickinson
The West Virginia School of Osteopathic Medicine
400 North Lee Street, Lewisburg, WV 24901, USA.
Tel: (304) 647-6370; E-mail: bdickinson@osteo.wvsom.edu
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