Although jawless vertebrates are apparently capable of adaptive immune responses, they have not been found to possess the recombinatorial antigen receptors shared by all jawed vertebrates. Our search for the phylogenetic roots of adaptive immunity in the lamprey has instead identified a new type of variable lymphocyte receptors (VLRs) composed of highly diverse leucine-rich repeats (LRR) sandwiched between amino- and carboxy-terminal LRRs. An invariant stalk region tethers the VLRs to the cell surface by means of a glycosyl-phosphatidyl-inositol anchor. To generate rearranged VLR genes of the diversity necessary for an anticipatory immune system, the single lamprey VLR locus contains a large bank of diverse LRR cassettes, available for insertion into an incomplete germline VLR gene. Individual lymphocytes express a uniquely rearranged VLR gene in monoallelic fashion. Different evolutionary strategies were thus used to generate highly diverse lymphocyte receptors through rearrangement of LRR modules in agnathans (jawless fish) and of immunoglobulin gene segments in gnathostomes (jawed vertebrates).
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We thank R. Bergstedt and W. Swink of the Hammond Bay Biological Station for assistance with lamprey biology and supply; G. Hines and the UAB Animal Resources Program staff for attending the lampreys; Y. Kubagawa for VLR sequencing; P. Burrows, H. Schroeder and E. Sorscher for discussion; and A. Brookshire for manuscript preparation. The work was supported by grants from the National Institutes of Health and the National Science Foundation. M.D.C. is an Investigator of the Howard Hughes Medical Institute and Z.P. was a recipient of the Cottrell postdoctoral award.
The authors declare that they have no competing financial interests.
Multiple alignment of 22 predicted VLR proteins from EST clones. (DOC 3785 kb)
ORF of a representative VLR. Nucleotide and predicted amino-acid sequence from clone LyEST2913, with indication of LRR structural motifs and their correspondence to exons 2-4 in the germline VLR, and the position of the stalk domain and GPI cleavage site. (DOC 2209 kb)
Multiple alignment of 112 VLR diversity regions PCR amplified from 13 lampreys. Genomic and RT–PCR clones from immunostimulated and unstimulated lampreys, including sorted single lymphocytes. Consists of top and bottom halves. (DOC 3991 kb)
PCR primers used in this study. Sequence and position of primers are provided for cDNA clone LyEST2913 (AY578059) and for the genomic VLR contig (AY577941). (DOC 25 kb)
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Pancer, Z., Amemiya, C., Ehrhardt, G. et al. Somatic diversification of variable lymphocyte receptors in the agnathan sea lamprey. Nature 430, 174–180 (2004). https://doi.org/10.1038/nature02740
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