Modeling the adaptive immune system: predictions and simulations

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

The cellular arm of the immune system consists of two parts; cytotoxic T lymphocytes (CTL), and helper T lymphocytes (HTLs). CTLs destroy cells that present non-self peptides (epitopes). HTLs are needed for B cells activation and proliferation to produce antibodies against a given antigen. CTLs on the other hand perform surveillance of the host cells, and recognize and kill infected cells, generally explained in Janeway et al. (2001) . Both CTL and HTL are raised against peptides that are presented to the immune cells by major histocompatibility complex (MHC) molecules, which are the most polymorphic of mammalian proteins. The human versions of MHCs are referred to as the human leucocyte antigen (HLA). The cells of an individual are constantly screened for such peptides by the cellular arm of the immune system. In the MHC class I pathway, class I MHCs presents endogenous antigens to T cells carrying the CD8 receptor (CD8þ T cells). To be presented, a precursor peptide is normally first generated by the large cytosomal protease complex called the proteasome (Loureiroa and Ploegha, 2006) . Generally, it then binds to the transporter associated with antigen processing (TAP) for translocation into the endoplasmic reticulum (ER), reviewed by Abele and Tampe´(2004) , but some peptides can enter the ER independently of TAP. This should be considered when dealing with virus-infected cells or tumors cells that might have reduced or absent TAP function. There are several ways that the peptide can enter the ER without TAP function depending on the origin and properties of the peptide. The most well-established model, however, is for proteins containing a signal peptide. Such proteins are translated directly into the ER through the Sec61 transporter complex and sometimes the cleaved-off signal peptide will end up in ER. This model is especially relevant for peptides binding to HLAs belonging to the abundant A2 HLA serotype where TAP-independent presentation is responsible for up to 10% of the A2 restricted epitopes, reviewed in . During or after the transport into the ER the peptide must bind to the MHC class I molecule (Stoltze et al., 2000; Zhang and Williams, 2006) before it can be transported to the cell surface through the golgi system. The most selective step in this pathway is binding of a peptide to the MHC class I molecule. In an older review, Yewdell and Bennink (1999) states that only 1 in 200 binds with an affinity strong enough to generate an immune response. This has been challenged, and it might be that up to 3% of the possible peptides bind strong enough to generate a subsequent immune response (Assarsson et al., 2007) . In another recent work of Moutaftsi et al. (2006) , however, it is found that of the 49 epitopes that are responsible for 95% of the total CD8þ T-cell response against a vaccinia challenge in mouse 90% binds MHC with an affinity stronger than 500 nM. In any case a peptide must go through the processes in a greater number than competing peptides to be immunodominant. The MHC is the most polymorphic gene system known. This polymorphism is a huge challenge for T-cell epitope discoveries, enhancing the need for bioinformatical analysis and resources. However, it also highly complicates immunological bioinformatics, as predictive methods for peptide MHC binding have to deal with the diverse genetic background of different populations and individuals. On a population basis, hundreds of alleles have been found for most of