Type 2 immune history trains lung macrophages for viral disease tolerance

Severe respiratory viral disease varies widely among individuals and often reflects immunopathology rather than inadequate pathogen control, suggesting that previous immune history can prime the lungs towards disease tolerance. Here we show that nerve- and airway-associated macrophages (NAMs), a subset of interstitial macrophages, expand ephemerally after type 2 inflammation induced by Nippostrongylus brasiliensis. We therefore hypothesized that NAMs acquire epigenetically imprinted trained immunity and tested this using a heterologous challenge model in which mice that were previously infected with N. brasiliensis were challenged 4–6 weeks later with lethal H1N1 influenza. All of the N. brasiliensis-conditioned mice survived, whereas all of the unconditioned controls succumbed by days 5–6. Protection occurred without reduced viral burden or enhanced T cell responses, instead tracking with reduced immunopathology, amplified type 2 cues, increased efferocytosis and accelerated tissue repair. Using NAM-DTR mice, we show that conditioned NAMs are necessary and sufficient for protection: depletion or replacement with unconditioned NAMs abrogated survival, whereas adoptive transfer of conditioned NAMs conferred tolerance without enhancing viral clearance. Genomic analyses implicated an IL-4–STAT6–PPARγ and ARG1 chromatin program that imprints a pro-resolving and reparative NAM state driving tissue repair, type 2 immunity and efferocytosis during lethal respiratory viral infections. Finally, meta-analysis of human lung single-cell atlases from cohorts of healthy individuals and individuals with IPF and COPD revealed context-dependent NAM-like repair programs. These findings establish local trained immunity in lung-resident macrophages as a mechanism of disease tolerance and a therapeutic entry point for severe inflammatory respiratory infections. Type 2 inflammation trains nerve- and airway-associated macrophages to confer disease tolerance against lethal influenza by limiting immunopathology and promoting tissue repair without enhancing viral clearance.