Abstract
SummaryMany hematopoietic cell types express CD1d and are capable of presenting glycolipid antigens to invariant natural killer T cells (iNKT cells). However, the question of which cells are the principal presenters of glycolipid antigens in vivo remains controversial, and it has been suggested that this might vary depending on the structure of a particular glycolipid antigen. Here we have shown that a single type of cell, the CD8α+ DEC-205+ dendritic cell, was mainly responsible for capturing and presenting a variety of different glycolipid antigens, including multiple forms of α-galactosylceramide that stimulate widely divergent cytokine responses. After glycolipid presentation, these dendritic cells rapidly altered their expression of various costimulatory and coinhibitory molecules in a manner that was dependent on the structure of the antigen. These findings show flexibility in the outcome of two-way communication between CD8α+ dendritic cells and iNKT cells, providing a mechanism for biasing toward either proinflammatory or anti-inflammatory responses.
Highlights
Natural killer T cells with invariant T cell receptor a chains are a conserved population that recognizes glycolipid antigens bound to CD1d, a lipid antigen-presenting molecule with structural similarities to major histocompatibility complex (MHC) class I proteins (Brennan et al, 2013; Rossjohn et al, 2012)
We have shown that a single type of cell, the CD8a+ DEC-205+ dendritic cell, was mainly responsible for capturing and presenting a variety of different glycolipid antigens, including multiple forms of a-galactosylceramide that stimulate widely divergent cytokine responses
These dendritic cells rapidly altered their expression of various costimulatory and coinhibitory molecules in a manner that was dependent on the structure of the antigen
Summary
Natural killer T cells with invariant T cell receptor a chains (iNKT cells) are a conserved population that recognizes glycolipid antigens bound to CD1d, a lipid antigen-presenting molecule with structural similarities to major histocompatibility complex (MHC) class I proteins (Brennan et al, 2013; Rossjohn et al, 2012). Studies of the prototypical glycolipid antigen of iNKT cells, an a-galactosylceramide (aGC) known as KRN7000, show the potential for iNKT cells to activate a range of immune effector functions in vivo. This occurs both through direct stimulation of iNKT cell functions and by transactivation of other effectors, most notably NK cells and dendritic cells (Brennan et al, 2013; Carnaud et al, 1999; Taraban et al, 2008). Derivatives of aGC containing truncated or unsaturated N-acyl chains induce responses in which cytokines typically associated with T helper-2 (Th2) cells predominate, and transactivation of NK cells is limited (Yu et al, 2005). On the other hand, replacing the O-glycosidic linkage of aGC with a nonhydrolyzable carbon linker gives a C-glycoside variant that induces cytokine responses biased toward cytokines characteristic of T helper 1 (Th1) cells, along with enhanced transactivation of NK cells and their secretion of interferon-g (IFN-g) (Schmieg et al, 2003)
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