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This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0900986v1 183/4/2475    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Baban, B. Articles by Mellor, A. L. PubMed PubMed Citation Articles by Baban, B. Articles by Mellor, A. L.

IDO Activates Regulatory T Cells and Blocks Their Conversion into Th17-Like T Cells¹

Babak Baban^*,, Phillip R. Chandler^*,, Madhav D. Sharma^*,¶, Jeanene Pihkala, Pandelakis A. Koni^*,, David H. Munn^*,¶ and Andrew L. Mellor^2,*,

^* Immunotherapy and Cancer Centers and Flow Cytometry Core Facility, Department of Pathology, Department of Medicine, and ^¶ Department of Pediatrics, Medical College of Georgia, Augusta, GA 30912

TLR ligands are effective vaccine adjuvants because they stimulate robust proinflammatory and immune effector responses and they abrogate suppression mediated by regulatory T cells (Tregs). Paradoxically, systemic administration of high doses of CpGs that bind to TLR9 ligands stimulated Tregs in mouse spleen to acquire potent suppressor activity dependent on interactions between programmed death-1 and its ligands. This response to CpG treatment manifested 8–12 h and was mediated by a rare population of plasmacytoid dendritic cells (CD19⁺ pDC) induced to express the immunosuppressive enzyme IDO after TLR9 ligation. When IDO was blocked, CpG treatment did not activate Tregs, but instead stimulated pDCs to uniformly express the proinflammatory cytokine IL-6, which in turn reprogrammed Foxp3-lineage Tregs to express IL-17. Thus, CpG-induced IDO activity in pDCs acted as a pivotal molecular switch that induced Tregs to acquire a stable suppressor phenotype, while simultaneously blocking CpG-induced IL-6 expression required to reprogram Tregs to become Th17-like effector T cells. These findings support the hypothesis that IDO dominantly controls the functional status of Tregs in response to inflammatory stimuli in physiological settings.

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 HD041187 and AI063402 (to A.L.M.) and CA103320, CA096651, and CA112431 (to D.H.M.).

² Address correspondence and reprint requests to Dr. Andrew L. Mellor, Immunotherapy Center, Medical College of Georgia, 1120, 15th Street, Augusta, GA 30912. E-mail address: amellor{at}mcg.edu

³ Abbreviations used in this paper: pDC, plasmacytoid dendritic cell; Treg, regulatory T cell; ODN, oligonucleotide; IFNAR/IFNR, IFN type 1/2 receptor; PD-1/L, programmed death-1/ligand; GCN2, general control nonderepressible-2; CHOP, C/EBP homologous protein; dLN, draining lymph node; KO, deficient (knockout); D-1MT, 1-methyl-D-tryptophan.

⁴ The online version of this article contains supplemental material.