Perinatal nicotine exposure disrupts hematopoietic stem cell development and elevates influenza severity in adulthood.

Developmental exposures profoundly shape lifelong health by altering disease resilience later in life. One potential cause of increased disease susceptibility is an altered immune system, originating in epigenetically maladaptive hematopoietic stem cells (HSCs). Here, we establish perinatal nicotine exposure (PNE) as a mouse model of developmental maladaptive immunity, wherein early-life environmental insults permanently alter HSCs. We show that PNE selectively disrupts the establishment of HSCs and tissue-resident, but not circulating, immune cells. Remarkably, the specific decrease of HSCs and lung-resident immune cells persists into adulthood. Single-cell transcriptomics revealed durable molecular reprogramming of adult PNE HSCs, with inverse regulation of positive trained immunity signatures. Functionally, adult PNE offspring challenged with respiratory virus exhibit exacerbated immune maladaptation, marked by increased weight loss, deteriorated lung pathology, hyper-permeability of pulmonary vasculature, tissue-resident macrophage depletion, and exaggerated neutrophil recruitment. Together, our findings establish that PNE imprints durable maladaptive immunity involving changes in HSCs and their progeny, suggesting a hematopoietic origin for the PNE-induced respiratory vulnerability.