title: Decreased T-cell receptor signaling through CARD11 differentially compromises forkhead box protein 3-positive regulatory versus T(H)2 effector cells to cause allergy.
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.
authors.affiliation: Department of Immunology, John Curtin School of Medical Research, Australian National University, Canberra, Australia.
authors.forename: John A
authors.initials: JA
authors.lastname: Altin
authors.forename: Lei
authors.initials: L
authors.lastname: Tian
authors.forename: Adrian
authors.initials: A
authors.lastname: Liston
authors.forename: Edward M
authors.initials: EM
authors.lastname: Bertram
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Goodnow
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Cook
mesh_terms: D000818:Animals; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism*; D003872:Dermatitis / Q000209:etiology / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006969:Hypersensitivity, Immediate / Q000209:etiology* / Q000276:immunology*; D007073:Immunoglobulin E / Q000097:blood; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology*
chemical_list: D053468:CARD Signaling Adaptor Proteins; C496467:Card11 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D016328:NF-kappa B; D011948:Receptors, Antigen, T-Cell; D007073:Immunoglobulin E