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Published ahead of print on September 4, 2003, doi:10.1165/rcmb.2003-0268OC

Am. J. Respir. Cell Mol. Biol., Volume 30, Number 3, March 2004, 311-318

A more recent version of this article appeared on March 1, 2004
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Submitted on July 18, 2003
Revised on August 25, 2003

CD11c+ Cells Modulate Pulmonary Immune Responses by Production of Indoleamine 2,3-dioxygenase1

Kena A Swanson1, Yan Zheng1, Kathleen M Heidler1, Teruaki Mizobuchi2, and David S Wilkes1*

1 Medicine, Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, United States, 2 Medicine, Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, United States; Thoracic Surgery, Chiba University, Chiba, Japan

* To whom correspondence should be addressed. E-mail: dwilkes{at}iupui.edu.

Interactions between antigen presenting cells and T cells can result in T cell activation or suppression. With the use of RNA analysis, HPLC, mixed leukocyte reactions (MLRs), and animal models, the current study reports that lung iAPCs (interstitial antigen presenting cells, CDllc+) suppress T cell responses in vitro and in vivo by production of indoleamine 2,3-dioxygenase3 (IDO), an enzyme that catabolizes tryptophan to its byproduct, kynurenine. IDO mRNA expression was unique to lung iAPCs, as cells similarly isolated from the liver and spleen did not express IDO constitutively, or in response to IFN-{gamma}. Lung iAPCs suppressed proliferation of allogeneic T cells, correlating with increased kynurenine levels; and blockade of IDO activity with 1-methyl-DL-tryptohan3 (1-MT) or addition of exogenous tryptophan recovered T cell proliferation in MLRs. In contrast, liver and splenic iAPCs were potent stimulators of T cells in MLRs, and IDO inhibition had no effect on T cell responses. In vivo studies showed that systemic blockade of IDO resulted in spontaneous proliferation in lung T cells and pulmonary inflammation. Finally, overexpressing IDO in lung transplants abrogated acute allograft rejection, a T cell-mediated disease. Collectively these data show that lung iAPCs contribute to local regulation of cellular immune responses by production of IDO.




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