Commensal and pathogenic organisms employ camouflage and mimicry to mediate mutualistic interactions and predator escape. However, the immune mechanisms accounting for the establishment and maintenance of symbiotic bacterial populations are poorly understood. A promising hypothesis suggests that molecular mimicry, a condition in which different organisms share common antigens, is a mechanism of establishing tolerance between commensals and their hosts. On this view, certain bacteria may mimic the structural features of some of their host’s T-cell receptors (TCRs), namely those that survive (...) thymic selection due to their lack of complementarity to self-antigens. With such “holoimmunity” the mimicking micro-organisms avoid immune recognition as the copied TCRs become mirror images of an extended super-organismal self, consisting of symbiotic and host antigens. Accordingly, analysis of genomic and metagenomic data suggests a tripartite mimicry between TCRs, self-antigens, and commensal antigens that would serve as the basis for immune tolerance between these populations. And conversely, in an autoimmune scenario, both symbiotic microbes and the mimicked host tissue would be targeted for immune destruction. (shrink)