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This Article Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0900582v1 183/11/6922    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 Request Permissions Google Scholar Articles by Castellaneta, A. Articles by Thomson, A. W. PubMed PubMed Citation Articles by Castellaneta, A. Articles by Thomson, A. W.

NOD2 Ligation Subverts IFN- Production by Liver Plasmacytoid Dendritic Cells and Inhibits Their T Cell Allostimulatory Activity via B7-H1 Up-Regulation¹

Antonino Castellaneta,^* Tina L. Sumpter,^* Lieping Chen, Daisuke Tokita,^* and Angus W. Thomson^2*

*Thomas E. Starzl Transplantation Institute, Department of Surgery, and Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261; and Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21231

The nucleotide-binding oligomerization domain (NOD)2/CARD15 protein, which senses muramyl dipeptide (MDP), a product of bacterial peptidoglycan, appears to play an important role in regulating intestinal immunity. Although the liver is exposed to gut-derived MDP, the influence of NOD2 ligation on hepatic APC, in particular dendritic cells (DC), is unknown. Freshly isolated mouse liver and spleen plasmacytoid (p)DC expressed higher levels of NOD2 message than conventional myeloid (m)DC. Following MDP stimulation in vivo, liver pDC, but not mDC, up-regulated expression of IFN regulatory factor 4 (IRF-4), a negative regulator of TLR signaling, and induced less allogeneic T cell proliferation and IFN- production. The adoptive transfer of liver pDC from MDP-treated mice failed to prime allogeneic T cells in vivo. By contrast, splenic DC IRF-4 levels and T cell stimulatory activity remained unchanged. Liver pDC from MDP-stimulated mice also displayed greater IB, cell surface B7-H1, and B7-H1 relative to CD86 than control liver pDC. No similar effects were observed for liver mDC or spleen DC. Absence of B7-H1 on liver pDC reversed the inhibitory effect of MDP. After ex vivo stimulation with LPS or CpG, liver pDC but not mDC from MDP-treated animals secreted less IL-12p70, IL-6, and TNF- and induced weaker allogeneic T cell proliferation than those from controls. Moreover, CpG-stimulated liver pDC from MDP-treated mice secreted less IFN- than their splenic counterparts, and systemic levels of IFN- were reduced in MDP-treated animals after CpG administration. These findings suggest that differential effects of NOD2 ligation on liver pDC may play a role in regulating hepatic innate and adaptive immunity.

Correspondence: ² Address correspondence and reprint requests to Dr. Angus W. Thomson, Departments of Surgery and Immunology, University of Pittsburgh School of Medicine, Thomas E. Starzl Transplantation Institute, 200 Lothrop Street, Biomedical Science Tower, W1540, Pittsburgh, PA 152123. E-mail address: thomsonaw{at}upmc.edu

¹ This work was supported by National Institutes of Health Grants R01 AI067541, R01 AI060994, and P01 81678 (to A.W.T.) and by the Roche Organ Transplantation Research Foundation (874279717). A.C. and T.L.S. are supported by Basic Science Fellowships from the American Society of Transplantation. D.T. was in receipt of a Uehara Foundation Fellowship.