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

Abstract

Background Allergy, the most common disease of immune dysregulation, has a substantial genetic component that is poorly understood. While complete disruption of 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 To elucidate how an inherited decrease in TCR signaling through CARD11, a critical scaffold protein that signals to NFκB transcription factors, results in spontaneous, selective accumulation of large numbers of Th2 cells. Methods ‘Unmodulated’ mice carry a Card11 single nucleotide variant (SNV) that decreases but does not abolish TCR/CD28 signaling to induce targets of NFκB. The consequences of this mutation on T cell subset formation in vivo were examined, and its effects within effector versus regulatory subsets were dissected by the adoptive transfer of wild-type cells, and by the examination of Foxp3-deficient unmodulated mice. Results Unlike the pathology-free boundary points of complete Card11 sufficiency or deficiency, unmodulated mice develop a specific allergic condition characterized by elevated IgE and dermatitis. The SNV partially decreases both the frequency of Foxp3+ T regulatory (Treg) cells and the efficiency of effector T cell formation in vivo. These intermediate effects combine to cause a gradual, selective expansion of Th2 cells. Conclusions Inherited reduction in the efficiency of TCR-NFκB signaling has graded effects on T cell activation and Foxp3+ Treg suppression that result in selective Th2 dysregulation and allergic disease.

Foxp3+ regulatory T cells exert asymmetric control over murine helper responses by inducing Th2 cell apoptosis

“…Under the model derived from the empirical data of the titration curve, the effect of quantitative decreases in Treg number is constant for Th1 responses but disproportionate for Th2 responses. In the current study we have focused on the purely quantitative effects of Tregs on Th bias; however, as shown by the Unmodulated Card11 mutation, 42 qualitative effects on Tregs are also able to release a strong Th2 response from Treg suppression. In the human disease context, polymorphisms altering number and function would be expected to interact to produce a spectrum of Treg functionality, which may operate akin to the titrated frequency curve in the experimental system here.…”

Ndfip1 mediates peripheral tolerance to self and exogenous antigen by inducing cell cycle exit in responding CD4+T cells

“…The 3A9 TCR Tg, insHEL Tg, Aire , and Foxp3 −/− mice were as described previously (37,39,61). Mice were either on the C57BL/6 background, the congenic C57BL/6.SJL-Ptprc CD45.1 background, or the congenic B10.BR and B10.BR.SJL-Ptprc CD45.1 strains, as indicated.…”

“…In vitro stimulation and staining for cell surface and intracellular proteins and CFSE dilution was performed as previously described (61). CTV labeling was done at room temperature as described (62) with slight modifications as described in SI Materials and Methods.…”

Omenn syndrome associated with a functional reversion due to a somatic second-site mutation in CARD11 deficiency

“…In these patients, IgE was normal and there were no lymphoproliferative manifestations. Late-onset dermatitis has also been reported in unmodulated mice carrying a single amino acid substitution in the coiled-coiled domain of CARD11 46 that does not occur in CARD11-null mice. 38,39 The skin infiltrates of unmodulated mice showed few T cells with no clonality (A.E., unpublished data, 2012).…”