Abstract
(English)
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Recognition of non peptidic ligands is not a unique property of yb T cells. We have started a systematic analysis of the T cell reactivities against different constituents of myelin in the peripheral blood and cerebrospinal fluid of patients with Multiple Sclerosis (MS). This disease is characterized by a variety of clinical forms and histological patterns, which have led some investigators to suggest that MS is a syndrome with similar clinical symptoms, but different etiopathogenesis. The histological picture common to the different MS forms is destruction of myelin with appearance of demyelinated plaques infiltrated with macrophages. Activated macrophages phagocytose myelin and present myelin constituents to T cells.
We have started to study the presence of cells reactive with glycolipids, which represent the major components of myelin, and have succeeded in establishing various bulk T cell lines reacting with self glycolipids. These cell lines have been cloned and glycolipid-specific clones have been isolated. We have found clones specific for gangliosides, sulfatide and b-galactosylceramide (b-GalCer), respectively. All the clones express ab TCR. The ganglioside and GalCer specific cells are CD8+, while the sulfatide specific ones are CD4+. These clones show a Th0 or Th1 functional phenotype and thus might participate to local inflammatory process in the brain. Two types of ganglioside specificities have been isolated: some cells react only to GM1, while other cells react to both GM1 and asialo-GM1. GM2 and asialo-GM2 are not recognized by these clones. Since these glycolipids differ only in the type of sugar, we conclude that this part of the molecule is discriminated by the TCR.
Using mAb inhibition assays and CD1a, b, c and d transfectants we have found that these cells are restricted by the non polymorphic CD1b molecule. We have also studied in detail the fine antigen-specificity and restriction of the sulfatide-specific cells. They do not react to b-GalCer nor to other glycolipids, which differ only in the monosaccharide structure and are restricted by the CD1a molecule, which was never shown to present exogenous ligandts to T cells. Finally, also b-GalCer-reactive cells are highly specific since they do not react to GlucoCer, nor to sulfatide. Their restriction is under investigation.
All together, these results make three important points. First, human T lymphocytes specific for self glycolipids do exist and can be isolated in culture. Second, several clones specific for different glycolipids discriminate small variations in the carbohydrate part of the antigen-structure. Thus, it is likely that the TCR of these cells make direct contact with the hydrophilic part of glycolipids. Third, both CD1a and CD1b present exogenously added self glycolipids to autoreactive T cells, suggesting that this family of MHC class I-like proteins may have evolved the function of presenting hydrophobic molecules to T cells.
Two important questions remain to be carefully addressed. First, the possible role of this type of autoreactive T cells in MS as well as in other autoimmune diseases, which at present is not at all clear. Second, whether these are common and important specificities or whether they are rare crossreactivities. Clear answers to both questions will reveal whether these T cell reactivities have an important function in immune response.
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