Libraries of synthetic glycopeptides in the characterization of hte T cell response to tumor associated mucin antigens

摘要

It has been well established that T cell stimulation is mediated by the presentation of peptide antigens by the MHC molecules on the surface of the antigen presenting cells. The peptides are fragments of proteins or even glycoproteins. The design of the binding groove of the MHC molecule is such that it only binds to peptides in their more or less extended coformation by interaction with anchor residues often towards the terminal ends. Carbohydrates and lipids do not interact with the MHC molecules and they belong to the group of T cell independent antigens unable to elicit a T cel response. However, the elution and analysis of peptides bound to the MHC molecules has revealed that glycan residues remaining from glycoprotein degradation could be attached to peptides bound to the MHC molecules [1]. It is therefore important to investigate the immunogenicity of glycopeptides, in particular the changes observed in the mucin glycosylation pattern in the case of e.g. colon cancer cells due to down regulation of enzymes leading to aberrant glycosylation [2]. Nothing is known about the specificity of the T cell response to glycans attached to peptides binding to MHC. The E~k restricted self peptide, VITAFNEGLK, from CBA/J mouse hemoglobin (67-76) is known to bind well MHC class II molecules, but is unable to stimulate the CD4~+ T cells to proliferate [3]. Conversion of such a non-immunogenic peptide into an immunogen by glycosylation would indicate that the T cell specificity was due to direct contact between the glycan and the binding domain of the TCR. Furthermore, by modifying the glycan in this mdoel for T cell-glycan recognition it would be possible to study the detailed molecular interactions betwen the glycan and the TCR, which in turn could lead to knowledge about the requirements for the efficient design of cancer vaccines.