Recognition of Lysophosphatidylcholine by Type II NKT Cells and Protection from an Inflammatory Liver Disease

Abstract

Summary Lipids presented by the major histocompatibility complex (MHC) class I-like molecule, CD1d, are recognized by natural killer T (NKT) cells, which can be broadly categorized into two subsets. The well-characterized type I NKT cells, express a semi-invariant T cell receptor (TCR) and can recognize both α- and β-linked glycolipids, whereas type II NKT cells are less well studied, express a relatively diverse TCR repertoire, and recognize β-linked lipids. Recent structural studies have shown a distinct mode of recognition of a self-glycolipid sulfatide bound to CD1d by a type II NKT TCR. To further characterize antigen recognition by these cells we have used the structural data and screened other small molecules able to bind to CD1d and activate type II NKT cells. Using plate-bound CD1d and APC-based antigen presentation assay we found that phospholipids such as lysophosphatidylcholine (LPC) can stimulate the sulfatide-reactive type II NKT hybridoma Hy19.3 in a CD1d-dependent manner. Using plasmon resonance studies we found that this type II NKT TCR binds with CD1d-bound LPC with micromolar affinities similar to that for sulfatide. Furthermore LPC-mediated activation of type II NKT cells leads to anergy induction in type I NKT cells and affords protection from ConA-induced hepatitis. These data indicate that, in addition to self-glycolipids, self-lysophospholipids are also recognized by type II NKT cells. Since lysophospholipids are involved during inflammation our findings have implications for not only understanding activation of type II NKT cells in physiological settings but also for the development of immune intervention in inflammatory diseases.

Lysophosphatidylcholine plays critical role in allergic airway disease manifestation

“…Although, some studies indicated that LPC might activate NKT cells3031, but, the present study is the first in vivo report regarding activation of NKT cells by LPC in case of allergic airway disease. The down regulation of allergic airway disease parameters was due to blockage of CD1d-NKT signalling and not due to depletion of APCs2122.…”

Crosstalk between type II NKT cells and T cells leads to spontaneous chronic inflammatory liver disease

“…NKT cells have been shown to play either a pathogenic or protective role in inflammatory liver disease [32, 33]. However, most of these studies used a model of ConA-induced hepatitis which causes acute liver inflammation but does not reflect chronic disease seen in human AIH.…”

Natural killer T cells in multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis

“…32 The sulphatide-reactive vNKT cells also reacted with other self-lipids, including b-GlcCer and b-GalCer, 33 as well as with lysophospholipids such as lysophosphatidylcholine. 34 The TCRs of vNKT cells interact with CD1d-glycolipid complexes in a perpendicular manner and predominantly engage the ligand using the b-chain rather than the a-chain. 35 Like iNKT cells, vNKT cells develop in the thymus, with a requirement for CD1d expression by haematopoietic cells, as well as the adaptor protein SAP and the transcription factor promyelocytic leukaemia zinc finger.…”

“…8,29 Sulphatide and lysophosphatidylcholine also suppress concanavalin A-induced hepatitis mediated by iNKT cells. 34,39 Tools and experimental models to study NKT cells Because markers expressed by NKT cells are not uniquely expressed by these cells, multimeric CD1d molecules loaded with glycolipid antigens have been extensively employed to identify these cells. CD1d/a-GalCer-tetramers specifically identify iNKT cells, 40 whereas CD1d/sulphatide-tetramers interact with sulphatide-specific vNKT cells.…”