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Systemic Control of Plasmacytoid Dendritic Cells by CD8⁺ T Cells and Commensal Microbiota¹

Daisuke Fujiwara^*, Bo Wei^*, Laura L. Presley, Sarah Brewer^*, Michael McPherson^*, Michael A. Lewinski^*, James Borneman and Jonathan Braun^2,*

^* Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095; and Department of Plant Pathology and Microbiology, University of California at Riverside, CA 92521

The composition of the intestinal microbial community is a distinctive individual trait that may divergently influence host biology. Because dendritic cells (DC) regulate the quality of the host response to microbiota, we evaluated DC in mice bearing distinct enteric microbial communities divergent for colitis susceptibility. Surprisingly, a selective, systemic reduction of plasmacytoid dendritic cells (pDC) was observed in isogenic mice with different microbiota: restricted flora (RF) vs specific pathogen free (SPF). This reduction was not observed in germfree mice, suggesting that the pDC deficiency was not simply due to a lack of intestinal microbial products. The microbial action was linked to cytotoxic CD8⁺ T cells, since pDC in RF mice were preserved in the CD8^–/– and perforin^–/– genotypes, partially restored by anti-CD8β Ab, and augmented in SPF mice bearing the TAP^–/– genotype. Direct evidence for pDC cytolysis was obtained by rapid and selective pDC depletion in SPF mice transferred with RF CD8⁺ T cells. These data indicate that commensal microbiota, via CTL activation, functionally shape systemic immune regulation that may modify risk of inflammatory disease.

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 DK46763 (to J.B. and M.K.), DK69434 (to J.B. and B.W.), GM07185 (to M.M.), AI52031 (to S.B.), and CA016042 (Jonsson Comprehensive Cancer Center Flow Cytometry); the Crohn’s and Colitis Foundation of America (to B.W.); and the Broad Medical Research Foundation (to J.B.). The germfree animal facility at the Center for Gastrointestinal Biology and Disease, North Carolina State University, was supported by Grant P30 DK349870 from National Institutes of Health.

² Address correspondence and reprint requests to Dr. Jonathan Braun, Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095-1732. E-mail address: jbraun{at}mednet.ucla.edu

³ Abbreviations used in this paper: DC, dendritic cell; mDC, myeloid DC; GF, germfree; MLN, mesenteric lymph node; pDC, plasmacytoid DC; RF, restricted flora; SPF, specific pathogen free; MHCII, MHC class II.