iNKT Cell Emigration out of the Lung Vasculature Requires Neutrophils and Monocyte-Derived Dendritic Cells in Inflammation

Abstract

iNKT cells are a subset of innate T cells that recognize glycolipids presented on CD1d molecules and protect against a variety of bacterial infections including S. pneumoniae. Using lung intravital imaging, we examined the behavior and mechanism of pulmonary iNKT cell activation in response to the potent iNKT cell ligand α-galactosylceramide or during S. pneumoniae infection. In untreated mice the major fraction of iNKT cells resided in the vasculature, but a small critical population resided in the extravascular space in proximity to monocyte-derived DCs. Administration of either α-GalCer or S. pneumoniae, induced CD1d dependent rapid recruitment of neutrophils out of the vasculature. This neutrophil exodus paved the way for extravasation of iNKT cells from the lung vasculature via CCL17. Depletion of monocyte-derived DCs abrogated both the neutrophil and subsequent iNKT cell extravasation. Moreover, impairing iNKT cell migration out of the lung vasculature by blocking CCL17 greatly increased susceptibility to S. pneumoniae infection, suggesting a critical role for the secondary wave of iNKT cells in host defense.

Pathogenesis of severe pneumonia

“…Intravital imaging of invariant natural killer T (iNKT) cells in the mouse lung revealed exciting new traffic patterns for innate lymphocytes. We learned that the majority of iNKT cells in the uninfected lung are intravascular, but that infection or inflammation triggers rapid diapedesis of these cells (20). Antigen presentation by dendritic cells to the small subset of iNKT cells initially in the interstitium resulted in local extravasation of neutrophils, and these migrating neutrophils synthesized CCL17 and the migration of intravascular iNKT cells into the tissues (20).…”

Recent advances in understanding neutrophils

“…The blockade of this mechanism resulted in worse outcomes to the infection 85 . A recent study identifies a similar guidance role for neutrophils in iNKT cell recruitment out of the lung 86 . In response to Streptococcus pneumoniae infection, iNKT migration out of the vasculature and subsequent activation in the interstitial space was dependent on prior transmigration of neutrophils.…”

“…In response to Streptococcus pneumoniae infection, iNKT migration out of the vasculature and subsequent activation in the interstitial space was dependent on prior transmigration of neutrophils. This mechanism was mediated by neutrophil release of CCL17, and blocking this signal disrupted iNKT localization and activation and increased susceptibility to S. pneumoniae infection 86 . In fact, simply using the neutrophil chemokine CXCL1 to elicit neutrophil migration out of the pulmonary vasculature also induced iNKT cell emigration.…”

The interaction between invariant Natural Killer T cells and the mucosal microbiota

“…71,73 iNKT cells are more frequent in the lung than in the secondary lymphatics, 24 with a strong influx from the blood following lung inflammation. 74 There is strong evidence for a major role for iNKT cells in regulating immune and inflammatory responses in the respiratory system. They are important contributors for most asthma models and have been implicated in the pathogenesis of human asthma.…”