Selected before selection: A case for inherent antigen bias in the T cell receptor repertoire

T cell receptor recombination is frequently described as a random or semi-random process that belies the now well-established principle that recombination is extremely biased towards the generation of particular receptor chains. Here we describe the experimental and theoretical work arising from new TCR repertoire sequencing approaches, including the recognition of high rates of public receptors across individuals, estimates of the size and distribution of receptors in the naive repertoire, and the roles of evolutionary, thymic, and peripheral selection in generating public, pathogen-specific responses. Molecular studies of recombination that have identified epigenetic, transcriptional, and topological contributions to variable segment usage are presented as examples of possible mechanisms shaped by natural selection to bias the TCR repertoire. Lastly, we suggest experimental approaches that might contribute to resolving some of the controversies in these areas.