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This Article Full Text Full Text (PDF) All Versions of this Article: jimmunol.0901030v1 183/9/5694    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 Zeituni, A. E. Articles by Cutler, C. W. PubMed PubMed Citation Articles by Zeituni, A. E. Articles by Cutler, C. W.

Targeting of DC-SIGN on Human Dendritic Cells by Minor Fimbriated Porphyromonas gingivalis Strains Elicits a Distinct Effector T Cell Response¹

Amir E. Zeituni,² Ravi Jotwani,^2* Julio Carrion,^* and Christopher W. Cutler^3*

^*Department of Periodontics and Implantology, School of Dental Medicine and Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, NY 11794

The oral mucosal pathogen Porphyromonas gingivalis expresses at least two adhesins: the 67-kDa mfa-1 (minor) fimbriae and the 41-kDa fimA (major) fimbriae. In periodontal disease, P. gingivalis associates in situ with dermal dendritic cells (DCs), many of which express DC-SIGN (DC-specific ICAM-3 grabbing nonintegrin; CD209). The cellular receptors present on DCs that are involved in the uptake of minor/major fimbriated P. gingivalis, along with the effector immune response induced, are presently unclear. In this study, stably transfected human DC-SIGN^+/– Raji cell lines and monocyte-derived DCs (MoDCs) were pulsed with whole, live, wild-type Pg381 or isogenic major (DPG-3)-, minor (MFI)-, or double fimbriae (MFB)-deficient mutant P. gingivalis strains. The influence of blocking Abs, carbohydrates, full-length glycosylated HIV-1 gp120 envelope protein, and cytochalasin D on the uptake of strains and on the immune responses was determined in vitro. We show that the binding of minor fimbriated P. gingivalis strains to Raji cells and MoDCs is dependent on DC-SIGN, whereas the double fimbriae mutant strain does not bind. Binding to DC-SIGN on MoDCs is followed by the internalization of P. gingivalis into DC-SIGN-rich intracellular compartments, and MoDCs secrete low levels of inflammatory cytokines and remain relatively immature. Blocking DC-SIGN with HIV-1 gp120 prevents the uptake of minor fimbriated strains and deregulates the expression of inflammatory cytokines. Moreover, MoDCs promote a Th2 or Th1 effector response, depending on whether they are pulsed with minor or major fimbriated P. gingivalis strains, respectively, suggesting distinct immunomodulatory roles for the two adhesins of P. gingivalis.

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 study was supported by U.S. Public Health Service, National Institutes of Health/National Institute of Dental and Cranial Research Grants R01 DE014328 (to C.W.C.), F31 DE020014 (to A.E.Z.), and K23 DE018187 (to J.C.).

² A.E.Z. and R. J. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Christopher W. Cutler, Department of Periodontics, School of Dental Medicine, Stony Brook University; Stony Brook, NY 11794-8703. E-mail address: ccutler{at}notes.cc.sunysb.edu

⁴ Abbreviations used in this paper: DC, dendritic cell; CBA, cytometric bead array; CM, Chiang Mai; CP, chronic periodontitis; DC-SIGN, DC-specific ICAM-3 grabbing nonintegrin; maj, major; min, minor; MoDC, monocyte-derived DC; MOI, multiplicity of infection; OLF, oral lymphoid foci; Pg, Porphyromonas gingivalis; PRR, pattern recognition receptor; Raji-DCS, DC-SIGN positive Raji cell.