The Journal of Experimental Medicine
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Published online
doi:10.1084/jem.20061737
The Journal of Experimental Medicine, Vol. 204, No. 2, 441-452
The Rockefeller University Press, 0022-1007 $30.00
© Shamshiev et al.
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ARTICLE

 Dyslipidemia inhibits Toll-like receptor–induced activation of CD8{alpha}-negative dendritic cells and protective Th1 type immunity

Abdijapar T. Shamshiev1, Franziska Ampenberger1, Bettina Ernst1, Lucia Rohrer2, Benjamin J. Marsland1, and Manfred Kopf1

1 Molecular Biomedicine, Institute of Integrative Biology, Swiss Federal Institute of Technology Zürich, 8952 Zürich, Switzerland
2 Institute of Clinical Chemistry, University Hospital Zürich, 8057 Zürich, Switzerland

CORRESPONDENCE Manfred Kopf: manfred.kopf{at}ethz.ch OR Abdijapar Shamshiev: japar.shamshiev{at}env.ethz.ch

Environmental factors, including diet, play a central role in influencing the balance of normal immune homeostasis; however, many of the cellular mechanisms maintaining this balance remain to be elucidated. Using mouse models of genetic and high-fat/cholesterol diet–induced dyslipidemia, we examined the influence of dyslipidemia on T cell and dendritic cell (DC) responses in vivo and in vitro. We show that dyslipidemia inhibited Toll-like receptor (TLR)–induced production of proinflammatory cytokines, including interleukin (IL)-12, IL-6, and tumor necrosis factor-{alpha}, as well as up-regulation of costimulatory molecules by CD8{alpha}– DCs, but not by CD8{alpha}+ DCs, in vivo. Decreased DC activation profoundly influenced T helper (Th) cell responses, leading to impaired Th1 and enhanced Th2 responses. As a consequence of this immune modulation, host resistance to Leishmania major was compromised. We found that oxidized low-density lipoprotein (oxLDL) was the key active component responsible for this effect, as it could directly uncouple TLR-mediated signaling on CD8{alpha}– myeloid DCs and inhibit NF-{kappa}B nuclear translocation. These results show that a dyslipidemic microenvironment can directly interfere with DC responses to pathogen-derived signals and skew the development of T cell–mediated immunity.

Abbreviations used: APC, allophycocyanin; BMDC, BM-derived DC; DLN, draining LN; HFCD, high-fat/cholesterol diet; HFD, high-fat diet; LDL, low-density lipoprotein; oxLDL, oxidized LDL; nLDL, native LDL; TBARS, thiobarbituric acid–reactive substrates; Tg, transgenic; TLR, Toll-like receptor; VLDL, very LDL.


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