CARD9 S12N facilitates the production of IL-5 by alveolar macrophages for the induction of type 2 immune responses

The adaptor CARD9 functions downstream of C-type lectin receptors (CLRs) for the sensing of microbial infection, which leads to responses by the T H 1 and T H 17 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 H 2 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 H 2 cell–mediated pathologic responses.