Abstract
BackgroundB cells play an important role in allergies through secretion of IgE. IL-4 receptor α (IL-4Rα) is key in allergic asthma and regulates type 2 cytokine production, IgE secretion, and airway hyperresponsiveness. IL-4 activation of B cells is essential for class switching and contributes to the induction of B effector 2 (Be2) cells. The role of Be2 cells and signaling via IL-4Rα in B cells is not clearly defined.ObjectiveWe sought to find out whether IL-4Rα–responsive B cells or Be2 function was essential in experimental allergic asthma.MethodsMice lacking IL-4Rα on B cells (mb1creIL-4Rα−/lox) or littermate controls (IL-4Rα−/lox) and mice lacking IL-4 or IL-4/IL-13 on B cells were sensitized and challenged with high-dose house dust mite (>10 μg) or with low-dose house dust mite (<3 μg). We also adoptively transferred naive IL-4Rα−/lox or IL-4Rα−/− B cells into μMT−/− mice a day before sensitization or a day before challenge. We analyzed lung inflammation, cellular infiltrate, and airway hyperresponsiveness.ResultsWe found that IL-4Rα signaling on B cells was important for optimal TH2 allergic immune responses mainly when the load of antigen is limited. IL-4Rα signaling on B cells was essential for germinal centers and in the effector phase of allergic responses. Be2 cells were essential in airway hyperresponsiveness, but not in other parameters.ConclusionsIL-4Rα signaling on B cells is deleterious in allergic asthma because it is required for optimal TH2 responses, Be2 function, germinal center formation, and T follicular helper cells, especially when the load of the antigen is limiting.
Highlights
B cells play an important role in allergies through secretion of IgE
We found that mice lacking IL-4 receptor a (IL-4Ra) on B cells had a moderately reduced airway resistance and elastance when compared with littermate mice sensitized and challenged with high-dose house dust mite (HDM) (Fig 1, B)
We further showed that IL-4Ra–responsive B cells regulate airway hyperresponsiveness (AHR), IgE secretion, and T follicular helper (TFH)-cell generation, and that B-cell–derived type 2 cytokines are required for optimal TH2 responses
Summary
To generate mice deficient of IL-4Ra only on B cells (mb1creIL-4Ra2/lox), we intercrossed homozygous mb1cre mice[31] with IL-4Ra2/232 on Balb/c background. We further mated mb1cre IL-4Ra2/2 mice with homozygous IL-4Ralox/lox mice[19] to generate hemizygous mb1creIL-4Ra2/lox[33] mice, which were backcrossed up to 10 generations in Balb/c background. Hemizygous littermates (IL-4Ra2/lox) expressing single functional IL-4Ra allele was used as a wild-type control in all experiments. Mice were housed in independently ventilated cages under specific pathogen-free conditions at the University of Cape Town Animal Facility. All mice were used at age 8 to 10 weeks, and animal procedures were performed according to strict recommendation by the South African Veterinary Council and were approved by the University of Cape Town Animal Ethics Committee All mice were used at age 8 to 10 weeks, and animal procedures were performed according to strict recommendation by the South African Veterinary Council and were approved by the University of Cape Town Animal Ethics Committee (reference no. 018/013).
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