T-cell autoreactivity against self glycosphingolipids in multiple sclerosis
T cells recognize a large variety of ligands, such as small peptides which are presented by major histocompatibility complex (MHC) class I and II proteins. Recognition of MHCpeptide complexes is mediated by the T-cell receptor (TCR), which is composed of covalently associated a and β chains. Human T cells also recognize non-peptidic ligands, which are represented by small phosphorylated non-peptidic metabolites,1-5 bacterial lipoglycans,6or α-galactosyl-ceramide, which is uniquely present in sponges.7 Recognition of these non-conventional ligands is very different from recognition of protein antigens as it does not require presentation by classical MHC molecules and, in some cases, is also independent of antigen processing. A well-studied system is represented by human T cells expressing the TCR γδ composed of the Vγ9 and Vδ2 chains, which recognize phosphorylated non-peptidic metabolites of both eukaryotic and prokaryotic origin.8 The entire Vγ9/Vδ2 population, which represents about 5-10% of circulating T cells, cross-reacts with a variety of phosphorylated ligands and is readily activated. This cell population is responsible for an efficient sentinel system which, upon detection of bacterial infection, immediately releases pro-inflammatory cytokines. A second important system of non-peptidic recognition is that of lipid and glycolipid molecules of self or bacterial origin.9 These ligands are recognized in association with CD1 antigen-presenting molecules, which are expressed on a variety of cell types. T cells capable of recognizing this class of ligands have been characterized extensively, while the molecular mechanisms of this type of antigen recognition and its physiological relevance are still poorly understood. In this chapter we describe the biological properties of this antigen-recognition system and discuss its possible relevance in multiple sclerosis (MS).