Positive selection of immune repertoires: A short further history

The importance of the negative selection of self-reacting cells from immune repertoires was easily recognized since it would militate against autoimmune disease. However, while the existence of positive selection in the auditioning of newly formed immune cells is now recognized, it is taking longer to understand its role. With the removal or suppression by negative selection of a subset of immune cells that self-react, would the specificities of remaining immune cells range widely to confront the universe of 'non-self' antigens, including some borne by potential microbial pathogens? Alternatively, from among those remaining immune cells, could some be picked out (positively selected) based on 'advanced knowledge' of some character likely to be common to those pathogens? To exploit 'holes' created by negative selection, it was predicted that pathogens would attempt to mimic their hosts by progressive stepwise mutation towards host 'self'-a process entailing passage through a host anti-'near-self-reactivity' arena. Anticipating this, those hosts that over evolutionary time 'learned' to positively select from developing immune repertoires, cells with reactivities against 'near-self', would be advantaged by natural selection. The benefits of this narrowing of the range of host immune reactivities are now clearer and may solve Burnet's paradox, which concerns the ability of an organism's immune cells to attack its own cancer cells. However, while supporting this in the context of T cell immunity, Manczinger and his colleagues now suggest that some wily pathogens may be exploiting their hosts' narrow defence foci by 'seeking', through mutation, dissimilarity from host 'self'.