The role of natural killer T cells in lung inflammation

Invariant NK T cells (iNKT) bridge the innate and adaptive immune response, being characterized by the ability to use invariant T cell receptors to recognize glycolipid antigens presented by CD1d, leading to an explosive cytokine effector response. As such it has been proposed that iNKT cells perform important roles as both effector and regulatory cells in a wide range of disease settings. These roles have been characterized in experiments depending on the use of iNKT-null mice, due to lack of either CD1d expression or J alpha 18 and the use of CD1d tetramers loaded with the model glycolipid antigen, a-galactosylceramide (alpha GalCer). Several studies have examined lung disease, infectious and allergic, in humans and mice. While the lung itself does not carry an exceptionally large population of iNKT cells (compared with, say, the liver), it does appear to be a site at which these cells can exert a profound effect. Several models of bacterial, fungal and viral murine lung infection have been investigated that have sometimes produced conflicting results. Abrogation of iNKT cell function in knockouts is often associated with disease exacerbation, indicating a regulatory role in lung infection. Studies in murine asthma models and in patients have similarly probed the role of iNKT cells in these settings. While there are again somewhat contradictory findings, evidence suggests a likely role for iNKT cells in mediating airway hyper-responsiveness (AHR), but probably not in Th2 polarization or lung eosinophilia. In marginally different models, administration of aGalCer has either ameliorated or exacerbated AHR. Different studies of BAL from human asthma patients show variously that there is either a very enlarged population of iNKT cells in the asthmatic lung, or that there is no significant difference from controls. Taken together, there are some observations that argue compellingly for an important role of iNKT cells in the lung, but resolution of some of the contradictory findings may await the development of reagents capable of providing alternative readouts of iNKT activation in these diverse disease settings. Copyright (C) 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.