Aggregation-prone peptides from within a non-self-protein homoaggregate are preferred for MHC association: Historical...

New technologies assist re-evaluation of hypotheses on generation of immune cell repertoires and distinctions of self from non-self. Findings include positive correlations between peptide propensities to aggregate and their binding to major histocompatibility complex (MHC) proteins. This recalls the hypothesis that foreign proteins may homoaggregate in host cytosols prior to releasing their peptides (p) to form pMHC complexes. Clues to this included aggregation-related phenomena associated with infections (rouleaux formation, pyrexia, certain brain diseases). By virtue of 'promiscuous' gene expression by thymic presenting cells - perhaps adapted from earlier evolving gonadal mechanisms - developing T cells monitor surface pMHC clusterings. This evaluates intracellular concentrations of the corresponding proteins, and hence, following Burnet's two signal principle, degrees of self-reactivity. After positive selection in the thymic cortex for reactivity with 'near-self', high-level pMHC clustering suffices in the medulla for negatively selection. Following Burnet's principle, in the periphery low-level clustering suffices for T cell stimulation and high-level clustering again provokes negative selection (immunological tolerance). For evolving intracellular pathogens, fine-tuned polymorphisms of their host species have limited to 'near-self' some mimicking adaptations. It is proposed that while entire pathogen proteins may have evolved to minimize their aggregability, the greater aggregability of their peptides remains partially hidden within. Two-step proofreading mechanisms in prospective hosts select proteins containing aggregable peptide for the generation of pMHC clusters at the surface of presenting cells. Through mutations, some proteins of pathogens and cancer cells tend to converge towards the host 'near-self' that its T cells have auditioned to address.