Decreased T-cell receptor signaling through CARD11 differentially compromises forkhead box protein 3-positive regulatory versus TH2 effector cells to cause allergy

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 kappa B (NF-kappa B) 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-kB. 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-kappa B 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. (J Allergy Clin Immunol 2011;127:1277-85.)