The ability to generate clonally diverse lymphocytes is a hallmark of the adaptive immune response in jawed vertebrates. This diversity is achieved by combining variable, diverse and joining gene segments in the immunoglobulin and T-cell receptor (TCR) loci. Various aspects of adaptive immune responses — for example, accelerated rejection of second skin grafts and antigen-specific agglutinins — have been identified in jawless vertebrates, but orthologues of the immunoglobulin, TCR and MHC genes have not be found. Now, a team from Max Cooper's laboratory has identified a novel type of variable lymphocyte receptor (VLR), the diversity of which is based on the number and variable sequence of leucine-rich repeats (LRRs).

To search for elements of the vertebrate immune system, the authors generated a subtracted cDNA library based on activated versus non-activated lymphocytes from sea lamprey larvae. The most common sequences contained variable numbers of diverse LRR motifs. Each VLR was shown to have eight different features: a signal peptide, an amino-terminal LRR, a variable number of diverse LRRs, a connecting peptide, a carboxy-terminal LRR, a conserved carboxyl terminus, a glycosylphosphatidylinositol anchor and a hydrophobic tail. Individual lymphocytes were found to express VLRs in a monoallellic fashion. Genomic analysis revealed a single germline gene that comprised only four exons and that could not encode the diverse full-length VLRs. The authors identified a series of variable diverse LRR sequences adjacent to the partial VLR gene; these are inserted into the partial VLR gene to generate mature VLR genes.

This study reveals that jawed and jawless vertebrates have evolved similar, but different, systems for generating variable lymphocyte receptors — one is a multigene recombinatorial strategy that uses gene segments encoding immunoglobulin domains, and the other is a somatic diversification strategy that is based on a single germline gene and the insertion of LRR sequences. The precise mechanism for the generation of the mature VLR in lampreys will be elucidated in future studies.