Compositional bias and mimicry toward the nonself proteome in immunodominant T cell epitopes of self and nonself antigens

We investigated whether and how molecular mimicry affects the shaping of th e helper T cell repertoire. We implemented an algorithm that measures the p robability of mimicry between epitopes of known immunogenicity and self or nonself proteomes. This algorithm yields 'similarity profiles', which repre sent the probability of matching between all contiguous overlapping peptide s of the antigen under examination and those in the proteome(s) considered. Similarity profiles between helper T cell epitopes (of self or microbial a ntigens and allergens) and human or microbial SWISSPROT collections were pr oduced. For each antigen, both collections yielded largely overlapping prof iles, demonstrating that self-nonself discrimination does not rely on quali tative features that distinguish human from microbial peptides. However, ep itopes whose probability of mimicry with self or nonself prevails are, resp ectively, tolerated or immunodominant and coexist within the same (auto-)an tigen regardless of its self/nonself nature. Epitopes ton self and nonself antigens) can cross-stimulate T cells at increasing potency as their simila rity with nonself augments. Mimicry, rather than complicating self-nonself discrimination, assists in the shaping of the immune repertoire and helps d efine the defensive or autoreactive potential of a T cell. Being a predicto r of epitope immunogenicity, it bears relevance to vaccine design.