Related Experiment Videos
Mechanisms of immunodominance in T-cell recognition, with applications to vaccine design
1Molecular Immunogenetics and Vaccine Research Section, National Cancer Institute, Bethesda, Maryland 20892.
Immunodominant T-cell antigenic sites can so dominate a response that their presence leads to high responsiveness and their absence to low responsiveness. Therefore, it is important to locate such sites for vaccine development. Factors that lead to immunodominance include features extrinsic to the structure of the site itself, such as the major histocompatibility complex (MHC) molecules of the host and the types of fragments produced by processing of the protein antigen before the T cell sees it. They also include factors intrinsic to the structure of the T-cell site, that determine a repertoire of potential immunodominant sites from which the extrinsic factors select a subset that will be immunodominant in a given individual. We have focused on one of these intrinsic factors, helical amphipathicity, that we have found to be a common feature among both helper and cytotoxic T-cell antigenic sites, suggesting that the same physical principles apply to sites seen in association with class I and class II MHC molecules. We have used this feature to locate immunodominant epitopes on the circumsporozoite protein of the Plasmodium falciparum malaria parasite and the envelope protein of the AIDS virus. Both helper and cytotoxic T-cell epitopes were identified. At least in the case of the helper T-cell sites, it was striking that the same sites in both the malaria and AIDS proteins studied that were immunodominant in the mouse were also immunodominant in the human, an indication that the same principles apply across species, and that the animal model will be useful for identifying sites to be used in vaccines for humans. These sites have been coupled with neutralizing antibody sites to produce artificial constructs that can elicit antibodies. It is hoped that the rational design of more complex versions of these artificial constructs will produce vaccines that are more effective than the natural pathogen proteins used in subunit vaccines, since such pathogen protein antigens have been selected through evolution to evade the immune system, not to optimize immunogenicity.
Immunodominant T-cell antigenic sites can so dominate a response that their presence leads to high responsiveness and their absence to low responsiveness. Therefore, it is important to locate such sites for vaccine development. Factors that lead to immunodominance include features extrinsic to the structure of the site itself, such as the major histocompatibility complex (MHC) molecules of the host and the types of fragments produced by processing of the protein antigen before the T cell sees it. They also include factors intrinsic to the structure of the T-cell site, that determine a repertoire of potential immunodominant sites from which the extrinsic factors select a subset that will be immunodominant in a given individual. We have focused on one of these intrinsic factors, helical amphipathicity, that we have found to be a common feature among both helper and cytotoxic T-cell antigenic sites, suggesting that the same physical principles apply to sites seen in association with class I and class II MHC molecules. We have used this feature to locate immunodominant epitopes on the circumsporozoite protein of the Plasmodium falciparum malaria parasite and the envelope protein of the AIDS virus. Both helper and cytotoxic T-cell epitopes were identified. At least in the case of the helper T-cell sites, it was striking that the same sites in both the malaria and AIDS proteins studied that were immunodominant in the mouse were also immunodominant in the human, an indication that the same principles apply across species, and that the animal model will be useful for identifying sites to be used in vaccines for humans. These sites have been coupled with neutralizing antibody sites to produce artificial constructs that can elicit antibodies. It is hoped that the rational design of more complex versions of these artificial constructs will produce vaccines that are more effective than the natural pathogen proteins used in subunit vaccines, since such pathogen protein antigens have been selected through evolution to evade the immune system, not to optimize immunogenicity.