Gaze into Cells MHCBinding Motifs

To "see" mutant or inappropriately expressed proteins in transformed cells, the immune system needs to "look" into these cells. This capability is provided by expression of MHC class I molecules associated with endogenous peptides. The mechanism of how antigen presenting cell(s) (APC) determines the restriction of effector T cells was uncovered by the Rammensee's group. As the author mentioned in his review on MHC-binding motifs in antigens, immunology owes two students, Olaf Rotzschke and Kirsten Folk, who were interested in the structure of peptides that interact with class I MHC molecules. To isolate these molecules, proteins of cell membranes were adsorbed on an immune affine column followed by the acidic elution and dissociation of MHC/p2-microglobulin/peptide complexes. The Edman sequencing of isolated peptides showed invariant amino acid residues near the C and N ends. Most importantly, the peptides bound by different allelic forms of MHC class I molecules had similar length but different allele-specific motifs (Falk et al. 1990, 1991a; Rotzschke, et al. 1990). The authors realized that they possess a powerful method for identification of the allele-specific sequences among a huge variety of peptides that could be derived from one antigenic protein (Falk et al. 1991b).

The fact that these motifs have been formed by "anchoring" amino acid residues necessary for high-affinity binding of the peptide with respective MHC molecule also indicated that APC expressing different MHC haplotypes can present various peptides of the same antigen (Rammensee et al. 1993; 1995). For example, the nucleoprotein of influenza virus contains the epitope that binds with H-2Kd in positions AA147-155 (TYQRTRALV) and with H-2Db in positions AA366-374 (MTEMNENSA). For human MHC molecules, the epitope for binding with HLA-A2 is within AA85-94 (KLGEFYNQM), and with HLA-A3 within AA265-273 (ILRGSVAHK), with HLA-B8 within AA380-388 (IAWYRSRLE), and with HLA-B27 in AA383-391 (SRYWAIRTR) (underlined are anchoring, i.e., motif forming, residues). The highest binding affinity of influenza virus nucleoprotein-derived peptides with H-2Db is achieved if the peptide has the canonical motif (Cerundolo et al. 1991). To see whether the expression of certain MHC molecule influenced the efficacy of peptide epitope presentation, the amounts of correctly processed Kb-restricted epitope of the minor histocompatibility antigen H-4b in H-2Kb-positive and-negative cells were estimated. The difference was 3000-fold, indicating an instructive role of MHC molecules in peptide-processing machinery (Wallny et al. 1992a). The mechanisms of peptide/MHC molecule association allowed predicting the structure of T cell peptide epitopes including tumor antigens (Rotzschke et al. 1991; Wallny et al. 1992b). Furthermore, these studies set rational molecular basis for an association between autoimmune diseases and certain MHC haplotypes (Vartdal et al. 1996; Kalbus et al. 2001; Munz et al. 2002). Finally, the ability of individual allelic products of MHC molecules to bind particular peptides of the pathogen directly links MHC with genetically determined immune response to pathogens.

The experience gained in the studies of MHC-binding motifs in MHC-associated peptides is currently used for constructing combinatorial peptide libraries. These tools make possible the positional screening for high-affinity ligands and cross-reacting ones for TCRs. Furthermore, making MHC tetramers can help to directly visualize the antigen-specific T lymphocytes (Wilson et al. 2004; Xu and Screaton 2002). There are a number of on-line services making possible the search for T cell epitopes among different protein sequences. One of them, RANKPEP service is a powerful mean for search of potential T cell epitopes presented by allelic forms of mouse and human MHC classes I and II molecules, taking into account protein degradation by proteasome (Reche et al. 2004). Obviously, the analysis of a specific protein reveals restricted number of epitopes capable to be presented by the MHC molecules of an individual. It assumes that some mutations in cancer-related genes can be invisible to the immune system making possible tumor escape from immu-nological surveillance.

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