1. Division of Developmental and Clinical Immunology, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA
2. Departments of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA
3. Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA
4. Microbiology, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA
5. Howard Hughes Medical Institute, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA
6. Molecular Genetics Program, Benaroya Research Institute at Virginia Mason, Seattle, Washington, 98101, USA
7. University of Michigan, Ann Arbor, Michigan 48109, USA

Correspondence to: Max D. Cooper^1,2,3,4,5 Email: max.cooper@ccc.uab.edu
All sequences reported here are deposited in GenBank under accession numbers AY577941–AY578059 and CK988414–CK988652.

Abstract

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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