Alternative Adaptive Immunity in Jawless Vertebrates

Abstract

Jawless vertebrates use variable lymphocyte receptors (VLRs) that are generated by RAG-independent combinatorial assembly of leucine-rich repeat cassettes for Ag recognition, instead of the Ig-based Ag receptors used by jawed vertebrates. The VLR genes encode for crescent-shaped proteins that use variable β-strands and a C-terminal loop to bind to Ags rather than the six CDR loops used by BCRs and TCRs. VLR mAbs have been isolated recently, which enabled the structure of VLR–Ag complexes to be defined. The jawless vertebrate adaptive immune system has many similarities to the Ig-based system of jawed vertebrates, including the compartmentalized development of B-like and T-like lymphocyte lineages that proliferate and differentiate into VLR-secreting plasmacytes and proinflammatory cytokine-producing cells in response to Ags. The definition of common features of the VLR-based and Ig-based systems offers fresh insight into the evolution of adaptive immunity.