CARD9S12N facilitates the production of IL-5 by alveolar macrophages for the induction of type 2 immune responses

Abstract

The adaptor CARD9 functions downstream of C-type lectin receptors (CLRs) for the sensing of microbial infection, which leads to responses by the T_H1 and T_H17 subsets of helper T cells. The single-nucleotide polymorphism rs4077515 at CARD9 in the human genome, which results in the substitution S12N (CARD9^S12N), is associated with several autoimmune diseases. However, the function of CARD9^S12N has remained unknown. Here we generated CARD9^S12N knock-in mice and found that CARD9^S12N facilitated the induction of type 2 immune responses after engagement of CLRs. Mechanistically, CARD9^S12N mediated CLR-induced activation of the non-canonical transcription factor NF-κB subunit RelB, which initiated production of the cytokine IL-5 in alveolar macrophages for the recruitment of eosinophils to drive T_H2 cell-mediated allergic responses. We identified the homozygous CARD9 mutation encoding S12N in patients with allergic bronchopulmonary aspergillosis and revealed activation of RelB and production of IL-5 in peripheral blood mononuclear cells from these patients. Our study provides genetic and functional evidence demonstrating that CARD9^S12N can turn alveolar macrophages into IL-5-producing cells and facilitates T_H2 cell-mediated pathologic responses.