A Gene-Dosage Effect for Interleukin-4 Receptor α-Chain Expression Has an Impact on Th2-Mediated Allergic Inflammation during Bronchopulmonary Mycosis

Interleukin (IL)-4 and IL-13 are key factors in the pathogenesis of bronchopulmonary mycosis induced in mice by infection with Cryptococcus neoformans. Both cytokines use the IL-4 receptor alpha-chain (IL-4R alpha). In this study, we investigated the role played by IL-4R alpha expression in susceptibility to pulmonary C. neoformans infection. IL-4R alpha(-/-) mice were extremely resistant. To characterize the effect of IL-4R alpha expression level on disease outcome, we generated IL-4R alpha(+/-) first-generation (F1) mice. IL-4R alpha(+/-) mice showed intermediate levels of IL-4R alpha expression, in contrast to higher levels in wild-type mice and no expression in IL-4R alpha(-/-) mice, indicating biallelic expression of the gene for IL-4R alpha (Il4ra). Concomitant with intermediate IL-4R alpha expression, F1 mice showed intermediate susceptibility associated with altered Th2/Th17 cytokine production, decreased immunoglobulin E levels, and reduced allergic inflammation. This indicates a gene-dosage effect of IL-4R alpha expression on susceptibility to bronchopulmonary mycosis. These data provide the basis for novel therapies antagonizing IL-4R alpha in Th2-related pulmonary infection and possibly also in asthma.