Dyslipidemia inhibits Toll-like receptor-induced activation of CD8α-negative dendritic cells and protective Th1 type immunity

Abdijapar T. Shamshiev, Franziska Ampenberger, Bettina Ernst, Lucia Rohrer, Benjamin J. Marsland, Manfred Kopf

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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-α, as well as up-regulation of costimulatory molecules by CD8α- DCs, but not by CD8α+ 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 CD8α- myeloid DCs and inhibit NF-κB 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. JEM

Original languageEnglish
Pages (from-to)441-452
Number of pages12
JournalJournal of Experimental Medicine
Volume204
Issue number2
DOIs
Publication statusPublished - 1 Feb 2007
Externally publishedYes

Cite this

Shamshiev, Abdijapar T. ; Ampenberger, Franziska ; Ernst, Bettina ; Rohrer, Lucia ; Marsland, Benjamin J. ; Kopf, Manfred. / Dyslipidemia inhibits Toll-like receptor-induced activation of CD8α-negative dendritic cells and protective Th1 type immunity. In: Journal of Experimental Medicine. 2007 ; Vol. 204, No. 2. pp. 441-452.
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Dyslipidemia inhibits Toll-like receptor-induced activation of CD8α-negative dendritic cells and protective Th1 type immunity. / Shamshiev, Abdijapar T.; Ampenberger, Franziska; Ernst, Bettina; Rohrer, Lucia; Marsland, Benjamin J.; Kopf, Manfred.

In: Journal of Experimental Medicine, Vol. 204, No. 2, 01.02.2007, p. 441-452.

Research output: Contribution to journalArticleResearchpeer-review

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