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

doi:10.1111/j.1530-0277.2010.01321.x

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

Journal article

Peer reviewed

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 and Annette J Schlueter

Alcoholism, clinical and experimental research, Vol.35(1), pp.47-59

01/2011

DOI: 10.1111/j.1530-0277.2010.01321.x

PMCID: PMC3058243

PMID: 21039629

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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.

Cell Differentiation

Receptors, Tumor Necrosis Factor - metabolism

Antigens, CD - immunology

Cricetinae

Spleen - immunology

Cytokines - metabolism

Lymphocyte Activation

Dendritic Cells - immunology

Mice, Inbred C57BL

Ethanol - administration & dosage

Rats

Spleen - cytology

Animals

Antigen Presentation

T-Lymphocytes - metabolism

Time Factors

Female

T-Lymphocytes - immunology

Mice

Alcoholism - immunology

Toll-Like Receptor 9 - metabolism

Cytokines - immunology

Disease Models, Animal

Details

Title: Subtitle: Mechanisms by which chronic ethanol feeding limits the ability of dendritic cells to stimulate T-cell proliferation
Creators: Ji Fan - Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, USA
Michelle R Edsen-Moore
Lucas E Turner
Robert T Cook
Kevin L Legge
Thomas J Waldschmidt
Annette J Schlueter
Resource Type: Journal article
Publication Details: Alcoholism, clinical and experimental research, Vol.35(1), pp.47-59
DOI: 10.1111/j.1530-0277.2010.01321.x
PMID: 21039629
PMCID: PMC3058243
NLM abbreviation: Alcohol Clin Exp Res
ISSN: 0145-6008
eISSN: 1530-0277
Publisher: Wiley; England
Grant note: R01 AA014406-05 / NIAAA NIH HHS R01 AA014406-01 / NIAAA NIH HHS R01 AA014406-03 / NIAAA NIH HHS R01 AA014406 / NIAAA NIH HHS R01 AA014405 / NIAAA NIH HHS AA014406 / NIAAA NIH HHS R01 AA014406-04 / NIAAA NIH HHS R01 AA014406-02 / NIAAA NIH HHS
Language: English
Date published: 01/2011
Academic Unit: Microbiology and Immunology; Pathology
Record Identifier: 9984047742402771

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