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J Allergy Clin Immunol. 2011 May;127(5):1277-85.e5. doi: 10.1016/j.jaci.2010.12.1081. Epub 2011 Feb 12.

Decreased T-cell receptor signaling through CARD11 differentially compromises forkhead box protein 3-positive regulatory versus T(H)2 effector cells to cause allergy.

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  • 1Department of Immunology, John Curtin School of Medical Research, Australian National University, Canberra, Australia.

Abstract

BACKGROUND:

Allergy, the most common disease of immune dysregulation, has a substantial genetic component that is poorly understood. Although complete disruption of T-cell receptor (TCR) signaling causes profound immunodeficiency, little is known about the consequences of inherited genetic variants that cause partial quantitative decreases in particular TCR-signaling pathways, despite their potential to dysregulate immune responses and cause immunopathology.

OBJECTIVE:

We sought to elucidate how an inherited decrease in TCR signaling through CARD11, a critical scaffold protein that signals to nuclear factor κB (NF-κB) transcription factors, results in spontaneous selective accumulation of large numbers of T(H)2 cells.

METHODS:

"Unmodulated" mice carry a Card11 single nucleotide variant that decreases but does not abolish TCR/CD28 signaling to induce targets of NF-κB. The consequences of this mutation on T-cell subset formation in vivo were examined, and its effects within effector versus regulatory T-cell subsets were dissected by the adoptive transfer of wild-type cells and by the examination of forkhead box protein 3 (Foxp3)-deficient unmodulated mice.

RESULTS:

Unlike the pathology-free boundary points of complete Card11 sufficiency or deficiency, unmodulated mice have a specific allergic condition characterized by increased IgE levels and dermatitis. The single nucleotide variant partially decreases both the frequency of Foxp3(+) regulatory T cells and the efficiency of effector T-cell formation in vivo. These intermediate effects combine to cause a gradual and selective expansion of T(H)2 cells.

CONCLUSIONS:

Inherited reduction in the efficiency of TCR-NF-κB signaling has graded effects on T-cell activation and Foxp3(+) regulatory T-cell suppression that result in selective T(H)2 dysregulation and allergic disease.

Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

PMID:
21320717
[PubMed - indexed for MEDLINE]
PMCID:
PMC3189857
Free PMC Article

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