Two unresolved problems facing models of the Self–Nonself discrimination

•Priming effector T-helpers.•Associative Recognition of Antigen.•Tolerance versus unresponsiveness.

Although the Associative (linked) Recognition of Antigen (ARA) model for a Self (S)–Nonself (NS) discrimination, now over 50 years old, is built on a solid conceptual and experimental base, two unsettled questions remain.1.How is ARA accomplished for T–T interactions?2.How does the immune system get started?In examining these questions, unanticipated aspects of the ARA Model itself had to be reconsidered. This essay spells out these problems and suggests possible solutions.