TCR-MHC/peptide interactions: kissing-cousins or a shotgun wedding?

The purpose of this Commentary is to put into modern-day perspective Jerne's hypothesis that antigen receptors encoded in the genome have been evolutionarily selected for their ability to react with major histocompatibility proteins and that the process of eliminating self reactivity is the catalyst for the generation of diversity of antigen receptors. In writing his hypothesis Jerne was trying to deal with the obsession of the immune system with the MHC, an obsession that was manifest in his days by the strong reactions of the immune system with allogeneic MHC proteins. However, Jerne's hypothesis also took on other issues that were not understood at the time--issues that included lymphocyte selection and tolerance, the generation of somatic diversity and the ability of the MHC to control responses to other antigens. In so doing, Jerne generated a hypothesis that accounted remarkably satisfactorily for what was known in 1971. Whilst the details of much of the hypothesis have since turned out to be incorrect, in his ideas Jerne did anticipate many of the most interesting and surprising findings of the subsequent 33 years.