The Role of CD1d-Restricted NKT Cells in the Clearance of Pseudomonas aeruginosa from the Lung Is Dependent on the Host Genetic Background

Abstract

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...

The host genetic background defines diverse immune-reactivity and susceptibility to chronic Pseudomonas aeruginosa respiratory infection

“…T cells orchestrate the activity of neutrophils and alveolar macrophages over the course of P. aeruginosa infection23. We found that at day 2, CD3 + and CD4 + T cell infiltrated the infected lungs to higher extents in C3H/HeOuJ resistant mice than in A/J susceptible ones (Fig.…”

Invariant natural killer T cells: front line fighters in the war against pathogenic microbes

“…Together these findings suggest a potentially important role for i NKT cells in mediating neutrophil responses for protection. Notably, in the pulmonary model of P. aeruginosa infection, a protective role for i NKT cells was later shown to only be true in BALB/c mice, and not C57BL/6 mice (Benoit et al 2015). This suggests different roles for the i NKT subsets, as BALB/c mice have more NKT2 cells, which might suppress neutrophil recruitment when activated, while C57BL/6 mice are more NKT1 subset biased.…”

The Pathophysiological Relevance of the iNKT Cell/Mononuclear Phagocyte Crosstalk in Tissues

“…iNKT cells react also to a number of pathogens involved in airway infections, including Sphingomonas capsulata ( 107 ), Mycobacterium tuberculosis ( 108 ), Pseudomonas aeruginosa ( 109 , 110 ), Streptococcus pneumoniae ( 111 ) and Influenza A virus ( 112 , 113 ), via involvement of local mononuclear phagocytic cells, particularly macrophages. During M. tuberculosis infection in mice, iNKT cells are activated upon interaction with macrophages presenting mycobacterium-specific lipids ( 108 ) and help controlling the bacterial load via GM-CSF production ( 114 ), which may promote an inflammatory response that ultimately leads to bacterial clearance.…”

“…A similar mechanism has been identified for P. aeruginosa , where iNKT cells stimulate increased phagocytic clearance of the bacteria in the lung by alveolar macrophages ( 109 ). Interestingly, in this context, iNKT cells have a stronger effect in controlling P. aeruginosa in BALB/c compared to C57BL6 mice ( 110 ). This difference can be explained by the different iNKT cell subsets that infiltrate the lungs of the two strains, as BALB/c mice contain an higher frequency of NKT1 subset compared to C57BL6 ( 24 , 115 ).…”