Abstract

Tissue-resident macrophages may be trained to confer an enhanced response to heterologous restimulation and thus foster versatile trained immunity (TI) against both infections and tumors. However, the key priming signals that contribute to such functional versatility in trained macrophages are not fully understood. Here, we show that influenza A virus (IAV) infection in mice induces lasting transcriptional imprints of acute type-I interferon (IFN-I) signaling in lung-resident alveolar macrophages (AMs) that confer balanced antibacterial and antitumor TI responses. In both IAV-infected mice and an ex vivo cytokine-mediated training system, IFN-I signaling is critical for the development of antitumor TI functions, although it limits antibacterial TI functions in AMs. Moreover, human AMs carrying transcriptional imprints of IFN-I signaling are associated with immune activation in lung cancer tissues. Our findings highlight IFN-I as a key priming signal required for the development of versatile TI functions in AMs with balanced antibacterial and antitumor potential.