Histocompatibility in Botryllus schlosseri and the origins of adaptive immunity.

The basal chordate, Botryllus schlosseri, undergoes a natural transplantation reaction that is controlled by a single, highly polymorphic locus called the fuhc. The fuhc is one of the most polymorphic loci ever described, with most populations having hundreds of alleles, and up to a thousand found worldwide. Two individuals are compatible if they share one or both alleles, while those with no shared alleles are incompatible; thus, Botryllus uses a missing-self recognition strategy to discriminate between up to a thousand histocompatibility ligands. Remarkably, this discriminatory capability, which rivals that of vertebrate adaptive immunity, is carried out by germline-encoded receptors; thus, the mechanisms that establish and maintain this remarkable specificity are not understood. Multiple complete haplotypes of the fuhc locus have recently been sequenced, and at least seven genes with characteristics that suggest a role in allorecognition have been identified, including ligands, receptors, and intracellular proteins that likely organize and tune signal transduction complexes. This includes a new receptor family called the fester co-receptors (FcoRs) that encode ITIM and hemITAM domains, linking allorecognition in Botryllus to canonical immune transduction pathways. This review will summarize our current understanding and working hypotheses on the cellular and molecular mechanisms that control this innate, highly polymorphic allorecognition response, and how those may have been co-opted during the evolution of adaptive immunity.