Lymphocyte repertoire selection and intracellular self/not-self discrimination: historical overview

Immunological self/not-self discrimination is conventionally seen as an extracellular event, involving interactions been receptors on T cells pre-educated to discriminate, and peptides bound to major histocompatibility complex proteins (pMHCs). Mechanisms by which not-self peptides might first be sorted intracellularly to distinguish them from the vast excess of self-peptides have long been called for. Recent demonstrations of endogenous peptide-specific clustering of pMHCs on membrane rafts are indicative of intracellular enrichment before surface display. The clustering could follow the specific aggregation of a foreign protein that exceeded its solubility limit in the crowded intracellular environment. Predominantly entropy-driven, this homoaggregation would co-localize identical peptides, so facilitating their collective presentation. Concentrations of self-proteins are fine-tuned over evolutionary time to avoid this. Disparate observations, such as pyrexia, and female susceptibility to autoimmune disease, can be explained in terms of the need to cosegregate cognate pMHC complexes internally prior to extracellular display.