Identification of the physiological antigen presenting cell for glycolipid antigens

Abstract

Abstract A major subset of T cells that recognize complexes formed by the binding of glycolipids to CD1d are called invariant natural killer T (iNKT) cells. Unlike conventional T cells that need to proliferate and differentiate to become activated effector T cells, iNKT cells exist as an effector population and start responding rapidly after glycolipid recognition. The prototypical iNKT stimulatory antigen is synthetic α-galactosylceramide (αGC), initially designated as KRN7000. Administration of this antigen in vivo results in the production of cytokines associated with both T helper type 1 (Th1) or type 2 (Th2) responses. Several variants of this antigen having different fatty acyl- and phytosphinganine chains have been synthesized and polarize the response towards a predominance of either Th1 or Th2 cytokines, and are therefore described as Th1- or Th2-biasing analogues. It is not clear how the Th1- or Th2-bias in iNKT mediated response is induced, although selective presentation by distinct cell types has been proposed as a possible mechanism. By visualizing glycolipid antigen presentation directly with monoclonal antibodies specific for complexes of αGC bound to CD1d, we showed that the CD8αPosDEC-205Pos dendritic cells were the major APCs in the spleen for a range of αGC analogues, irrespective of their chemical structures and cytokine biasing activities. We found that DCs presenting Th1-biasing agonists upregulated ligands for stimulatory NK receptor molecules, while Th2-agonist presenting cells showed a marked upregulation of ligands for inhibitory receptors. Furthermore, modulation of accessory immune proteins was dependent on CD1d, suggesting direct cell-cell interactions between DC and iNKT cells.