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Reduced Cytotoxic Function of Effector CD8⁺ T Cells Is Responsible for Indoleamine 2,3-Dioxygenase-Dependent Immune Suppression¹

Hanzhong Liu^*, Li Liu, Kaifeng Liu^*, Peyman Bizargity^*, Wayne W. Hancock and Gary A. Visner^2,*

^* Division of Pulmonary Medicine, Children’s Hospital Boston, Harvard Medical School, Boston, MA 02115; Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL 32610; and Department of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA 19104

Indoleamine 2,3-dioxygenase (IDO), a potent immunosuppressive enzyme, contributes to tumoral escape, immune tolerance, and protection against allograft injury. In this paper, we report that inhibition of CD8⁺ T cell-mediated cytotoxic function is an important mechanism behind IDO’s immune-modulating property. The experimental rat lung allograft proved attractive for evaluating effector CD8⁺ T cells. Enhanced IDO activity achieved by using a lung-tissue-targeted nonviral human IDO gene transfer approach reduced, but did not eliminate, infiltrating CD8⁺ T cells. Although CD8⁺ T cells existed in the IDO-high lung allografts, CD8⁺ T cells remained viable and could proliferate for an extended period. However, cells lost their ability to attack allogeneic donor lung cells in vivo and allogeneic target cells in vitro. The impaired cytotoxic function seen in the IDO-treated CD8⁺ T cells was accompanied by defects in production of granule cytotoxic proteins, including perforin and granzyme A and B. Furthermore, we discovered that IDO leads to an impaired bioenergetic condition in active CD8⁺ T cells via selective inhibition of complex I in the mitochondrial electron transfer chain. These intriguing findings provide a base for establishing a novel mode of IDO’s immune-suppressing action. Additionally, donor lung IDO delivery, a direct and/or leukocyte passenger effect, impaired CD8⁺ effector cell function.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants R03AI074646 and R01HL088191 (to G.A.V.).

² Address correspondence and reprint requests to Dr. Gary A. Visner, Division of Pulmonary Medicine, Children’s Hospital Boston, Harvard Medical School, 300 Longwood, Hunnewell Room 268, Boston, MA 02115. E-mail address: gary.visner{at}childrens.harvard.edu

³ Abbreviations used in this paper: IDO, indoleamine 2,3-dioxygenase; 1-mT, 1-methyltryptophan; ACR, acute cellular rejection; BLT, N--benzyloxycarbonyl-L-lysine thiobenzyl ester; DCIP, dichloroindophenol; m, mitochondrial membrane potential; ET, endothelin; GCN2, general control non-derepressible 2; hIDO, human IDO; OXPHOS, mitochondrial oxidative phosphorylation; PaO₂, partial pressure of oxygen; PawP, peak airway pressure; PEI, polyethylenimine; pET, ET-1 promoter.

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				R. B. Sorensen, P. t. Straten, and M. H. Andersen Comment on "Reduced Cytotoxic Function of Effector CD8+ T Cells Is Responsible for Indoleamine 2,3-Dioxygenase-Dependent Immune Suppression" J. Immunol., November 15, 2009; 183(10): 6040 - 6040. [Full Text] [PDF]