Another open question in T cell response is why roughly half of all foreign cell surface-presented antigens fail to raise a T cell response [3, 4, 21] . Tolerance to self-antigens could explain this lack of immunogenicity, in which case the degree of similarity to self-antigens should predict which foreign antigens are likely to be non-immunogenic. We examined this effect of self-tolerance on immunogenecity using our cross-reactivity model. First, a large set of self-antigens was defined, and secondly, a list of non-self (e.g., HIV) antigens was built, labeled as either immunogenic or nonimmunogenic according to experimental evidence (data obtained from the Los Alamos HIV database, see Materials and Methods). The expectation was that T cell clones, with high affinity for HIV peptides similar to self peptide(s), have been tolerized during thymic education via negative selection [22, 23] . Such TCRs should therefore not be present in the functional T cell repertoire thus causing tolerance to molecular mimics of self-peptides. We define a score of cross-reactivity to self as the maximum peptide similarity between the non-self antigen and the set of all selfantigens (see Materials and Methods) and test whether nonimmunogenic peptides have a higher cross-reactivity score to self when compared to immunogenic ones. We downloaded the human proteome from the NCBI website and identified a set of 230,460 potential HLA-A2 self-antigens (see Materials and Methods). Next, we downloaded the HIV proteome from the Los Alamos HIV database and predicted a set of potential HLA-A2 epitopes. 33 of the 91 predicted HIV candidate epitopes were annotated as A2 supertype restricted epitopes in the Los Alamos database of CTL HIV epitopes, while the remaining 54 of the HIV peptides were never identified as epitopes. Another four peptides were found to be immunogenic for other HLA alleles than HLA-A2. Since it would be wrong to tag these epitopes as ''non-immunogenic'', they were excluded from the data set. The 33 confirmed HLA-A2 epitopes were labeled: confirmed HIV epitopes and the remaining 54 possible non-immunogenic peptides were given the label: putative, non-immunogenic HIV peptides. It is possible that future studies reveal that a number of the putative nonimmunogenic HIV peptides do in fact elicit CTL responses in HLA-A2 + patients. Nevertheless, this set of HIV peptides should be enriched in HIV peptides that fail to generate CTL responses. Maximal similarity scores were computed between all 87 HIV peptides (33 immunogens and 54 putative non-immunogens) and the set of 230,460 predicted HLA-A2 self-epitopes. Fig. 4 shows a scatter plot of the 33 HIV immunogens (black diamonds) and 54 putative non-immunogens (open circles). The x-axis shows the predicted antigen presentation score (NetCTL) while the y-axis shows the estimated maximum similarity to the self-antigens S SELF (x,y) (see Materials and Methods). Immunogenic peptides tend to be less self-like, although the difference between immunogens and non-immunogens is not significant (p = 0.2, Mann-Whitney). Drawing a horizontal line at y = 0.85 separates the most self-similar HIV antigens from the rest (the results presented in Fig. 2B suggest that IFNc response would fall to a half when the similarity drops to 85%.) For the antigens that have a self-similarity score above 0.85, most (14/16) are classified as nonimmunogenic HIV antigens i.e. predicted epitopes not confirmed by experimental evidence (p-value,0.05, Fisher's exact test). Note, that the NetCTL score does not correlate with the maximal selfsimilarity score (p-value = 0.42, exact estimate) and the above difference between the immunogenic and non-immunogenic antigens is therefore not explained by the difference in the NetCTL scores. Repeating our analysis for HLA-A3 and HLA-B7, we found similar tendency of more-self-likeness among nonimmunogenic HIV-1 peptides (p,0.3 and p,0.45 respectively). Summarizing, these results suggest that similarity to self-antigens plays a role in discriminating immunodominant from cryptic peptides. 