On being the right size: antibody repertoire formation in the mouse and human

Abstract

The immune systems of all mammals include populations of B cells producing antibodies with incredibly diverse specificities. Repertoire diversity has been described as the "miracle of immunology," and it was long thought to be the result of essentially stochastic processes. Recently, however, analysis of high throughput gene sequencing data has shown that hard-wired biases in these processes result in antibody repertoires that are broadly predictable. The repertoires of mice and humans are both predictable, but they are strikingly different. In this review, features of the naïve antibody repertoires of the two species are contrasted. We show that the mouse repertoire includes a conspicuous population of public clonotypes that are shared by different individuals of an inbred strain. These clonotypes are the result of gene rearrangements that involve little gene processing. By skewing repertoire formation toward such sequences, which probably target commonly encountered pathogens, it may be that the relatively small mouse repertoire is appropriate and effective despite its size. Species like the mouse face challenges that are a direct consequence of their small body sizes and the limitations this places on the antibody arsenal-particularly early in ontogeny. We propose that it is the differences in the naïve repertoires of mice and humans, and the differences in the ways these repertoires are used, which ensure that the very different biological needs of the two species are met. The processes that contribute to repertoire formation may appear to be stochastic, but in both species, evolution has left little to chance.

Keywords: Antibody repertoires; Comparative immunology; Humoral immunity; Public clonotypes; Scaling and the immune system; V(D)J recombination.