Mechanisms by which chronic ethanol feeding limits the ability of dendritic cells to stimulate T-cell proliferation

Alcohol Clin Exp Res. 2011 Jan;35(1):47-59. doi: 10.1111/j.1530-0277.2010.01321.x. Epub 2010 Oct 6.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alcoholism / immunology*
  • Animals
  • Antigen Presentation
  • Antigens, CD / immunology
  • Cell Differentiation
  • Cricetinae
  • Cytokines / immunology
  • Cytokines / metabolism
  • Dendritic Cells / immunology*
  • Disease Models, Animal
  • Ethanol / administration & dosage*
  • Female
  • Lymphocyte Activation*
  • Mice
  • Mice, Inbred C57BL
  • Rats
  • Receptors, Tumor Necrosis Factor / metabolism
  • Spleen / cytology
  • Spleen / immunology
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism
  • Time Factors
  • Toll-Like Receptor 9 / metabolism


  • Antigens, CD
  • Cytokines
  • Receptors, Tumor Necrosis Factor
  • Tlr9 protein, mouse
  • Toll-Like Receptor 9
  • Ethanol