Mechanisms by Which Chronic Ethanol Feeding Limits the Ability of Dendritic Cells to Stimulate T-Cell Proliferation

Ji Fan, Michelle R. Edsen-Moore, Lucas E. Turner, Robert T. Cook, Kevin L. Legge, Thomas J. Waldschmidt, Annette J. Schlueter

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

Background: As initiators of immune responses, dendritic cells (DCs) are required for antigen (Ag)-specific activation of naïve T cells in the defense against infectious agents. The increased susceptibility to and severity of infection seen in chronic alcoholics could be because of impaired DCs initiation of naïve T-cell responses. Specifically, these DCs may not provide adequate Signals 1 (Ag presentation), 2 (costimulation), or 3 (cytokine production) to these T cells.Methods: Using the Meadows-Cook murine model of chronic alcohol abuse, the ability of ethanol (EtOH)-exposed DCs to stimulate T-cell proliferation, acquire and process Ag, express costimulatory molecules, and produce inflammatory cytokines was assessed.Results: Normal naïve T cells primed by EtOH-exposed DCs showed decreased proliferation in vitro and in vivo, compared to water-fed control mice. These EtOH-exposed DCs, after activation by CpG or tumor necrosis factor alpha (TNFα), were less able to upregulate costimulatory molecules CD40, CD80, or CD86, and produced less IL-12 p40, TNFα, and IFNα than DCs from water-fed mice. TLR9 and TNF receptor expression were also reduced in/on EtOH-exposed DCs. No evidence of defective Ag acquisition or processing as a result of EtOH feeding was identified.Conclusions: Inadequate proliferation of normal T cells following stimulation by EtOH-exposed DCs is likely a result of diminished Signal 2 and Signal 3. Lack of adequate inflammatory stimulation of EtOH-exposed DCs because of diminished receptors for inflammatory mediators appears to be at least partially responsible for their dysfunction. These findings provide a mechanism to explain increased morbidity and mortality from infectious diseases in alcoholics and suggest targets for therapeutic intervention.

Original languageEnglish (US)
Pages (from-to)47-59
Number of pages13
JournalAlcoholism: Clinical and Experimental Research
Volume35
Issue number1
DOIs
StatePublished - Jan 2011

Keywords

  • Antigen Processing
  • Costimulatory Molecules
  • Cytokines
  • Dendritic Cells
  • Mouse

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Toxicology
  • Psychiatry and Mental health

Fingerprint Dive into the research topics of 'Mechanisms by Which Chronic Ethanol Feeding Limits the Ability of Dendritic Cells to Stimulate T-Cell Proliferation'. Together they form a unique fingerprint.

  • Cite this