The genes encoding the major histocompatibility (MHC) molecules are among the most polymorphic genes known in vertebrates. Since MHC molecules play an important role in the induction of immune responses, this polymorphism is probably due to selection for increased protection of hosts against pathogens. In contrast to the large population diversity of MHC molecules, each individual expresses only a limited number of different MHC molecules. This is widely believed to represent a trade-off between maximizing the detection of foreign antigens, and minimizing the loss of T cell clones during self tolerance induction in the thymus.
Here we review theoretical models and bioinformatic analyse that we have developed to study the diversity of MHC molecules, both at the individual and at the population level. We have found that thymic selection does not limit the individual MHC diversity. Expression of extra MHC types decreases the number of clones surviving negative selection, but increases the number of positively selected clones. The net effect is that the number of clones in the functional T cell repertoire would increase if the MHC diversity within an individual were to exceed its normal value.
It has been proposed that the large population diversity of the MHC is due to selection favoring MHC heterozygosity. Since MHC heterozygous individuals can present more peptides to the immune system, they are better protected against infections than MHC homozygous individuals. Using a population genetics model, we found however that this heterozygote advantage is insufficient to explain the large degree of MHC polymorphism found in nature. Only if all MHC alleles in the population were to confer unrealistically similar fitness contributions to their hosts, could heterozygote advantage account for an MHC polymorphism of more than ten alleles. By predicting the immunodominant peptides from various common viruses we found that different MHC alleles are expected to provide quite different levels of protection. Thus, additional selection pressures seem to be involved. Using a computer simulation model we found that frequency-dependent selection by host-pathogen coevolution provides such an additional selection pressure that can account for realistic degrees of polymorphism of the MHC. The polymorphism of the MHC thus seems a result of host-pathogen coevolution, giving rise to a large population diversity despite the limited degree of MHC diversity within individuals.
- Cell Repertoire
- Heterozygote Advantage
- Marginal Fitness
- Fitness Contribution
- Host Population Size
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