dPseudomonas aeruginosa is an important human opportunistic pathogen, accounting for a significant fraction of hospital-acquired lung infections. CD1d-restricted NKT cells comprise an unusual innate-like T cell subset that plays important roles in both bacterial and viral infections. Previous reports have differed in their conclusions regarding the role of NKT cells in clearance of P. aeruginosa from the lung. Since there is significant strain-dependent variation in NKT cell number and function among different inbred strains of mice, we investigated whether the role of NKT cells was dependent on the host genetic background. We found that NKT cells did indeed play a critical role in the clearance of P. aeruginosa from the lungs of BALB/c mice but that they played no discernible role in clearance from the lungs of C57BL/6 mice. We found that the strain-dependent role of NKT cells was associated with significant strain-dependent differences in cytokine production by lung NKT cells and that impaired clearance of P. aeruginosa in BALB/c CD1d ؊/؊ mice was associated with an increase in neutrophil influx to the lung and increased levels of proinflammatory cytokines and chemokines after infection. Finally, we found that the role of alveolar macrophages was also dependent on the genetic background. These data provide further support for a model in which the unusually high level of variability in NKT cell number and function among different genetic backgrounds may be an important contributor to infectious-disease susceptibility and pathology. P seudomonas aeruginosa is a ubiquitous Gram-negative bacterium that is an important human opportunistic pathogen. P. aeruginosa infection is responsible for a significant fraction of hospital-acquired infections (1). It commonly affects patients with impaired lung function due to disease (e.g., cystic fibrosis) or mechanical ventilation. While neutrophils appear to be the principal mediators of host resistance to P. aeruginosa in the lung (2), evidence suggests that other leukocyte subsets of both the innate and adaptive arms of the immune system also play significant roles in the host clearance of Pseudomonas bacteria from the lungs (1, 3).CD1d-restricted NKT cells comprise an unusual innate-like ␣␤ T cell subset that plays important roles in both bacterial and viral infections (4, 5). NKT cells can be activated directly, through the recognition of glycolipids presented by CD1d (6), or indirectly, through interleukin-12 (IL-12)) and IL-18 produced upon recognition of pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (7). Once activated, NKT cells can rapidly produce large amounts of a wide variety of cytokines and chemokines which have significant modulatory effects during the early stages of infection on the function of leukocytes of both the innate and adaptive arms of the immune system, including neutrophils and macrophages (8-10). Previous investigations into the role of NKT cells in the host response to P. aeruginosa infection of the lungs have yi...