Modeling the adaptive immune system: predictions and simulations

Lundegaard, Claus; Lund, Ole; Kesmir, Can; Brunak, Søren; Nielsen, Morten

the HLA encoding loci (1839 in release 2.17.0 of the IMGT/HLA Database, http://www.ebi.ac.uk/imgt/hla/). In a given individual either one or two different alleles are expressed per locus depending on whether the same (in homozygous individuals) or two different (in heterozygous individuals) alleles are coded for on the two different chromosomes. The number of MHC expressing loci, however, differs highly among species. While a fully heterozygous human has six different MHC class I genes, a rhesus macaque may host up to 22 active MHC class I genes (Daza-Vamenta et al., 2004) . Each MHC allele binds a very restricted set of peptides and the polymorphism affects the peptide binding specificity of the MHC; one MHC will recognize one part of the peptide space, whereas another MHC will recognize a different part of this space. The very large number of different MHC alleles makes reliable identification of potential epitope candidates an immense task if all alleles are to be included in the search. However, many MHC alleles share a large fraction of their peptide-binding repertoire, and it is often possible to find promiscuous peptides, which bind to a number of HLA alleles. A way of reducing the problem is to group all the different alleles into supertypes in a manner so that all the alleles within a given supertype have roughly the same peptide specificity (Hertz and Yanover, 2007; Reche and Reinherz, 2004; Sette and Sidney, 1998, 1999) . This allows the search to be limited to a manageable representative set. Representing a supertype by a well-studied allele might lead to selection of epitopes that is very restricted to this allele, but not to any other alleles within the supertype. Thus another, and potentially more rational approach, would be to select a limited set of peptides restricted to as many alleles as possible. This should be within reach with new methods that directly predict epitopes that can bind to different alleles (promiscuous epitopes) (Brusic et al., 2002) , or pan-specific approaches that can make predictions for all alleles where the sequence is known (Jojic et al., 2006; Nielsen et al., 2007a) . When the peptide-MHC complex is presented on the surface of the cell, it might bind to a CD8þ T cell with a fitting T-cell receptor (TCR). If such a TCR clone exists depends on, among other factors, if the TCR-peptide complex is too similar to MHC-peptide complexes generated with peptides from the host proteome (selfpeptides). This effect is called tolerance and might be broken by so-called self-epitopes, reviewed by Andersen et al. (2006) . B cells must be activated to produce antibodies against a given antigen, and helper T cells specific for peptides from the antigen must be activated to get a strong B-cell response. The epitope recognized by the helper T cell is usually somehow connected to the epitope that is recognized by the B cell, but the two cells do not necessarily recognize overlapping epitopes. T cells can recognize internal peptides that do not need to be a part of the surface-surface interactions with the B-cell receptor. Actually, the T-cell and the B-cell epitopes might not even come from the same protein (Janeway et al., 2001) . The peptides recognized by the CD4þ T cells are presented by the MHC class II molecule, and peptide presentation on MHC class II molecules follow a different path than the MHC class I presentation pathway (Castellino et al., 1997) : MHC class II molecules associate with the invariant ch