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Somatic diversification of variable lymphocyte receptors in the agnathan sea lamprey

Naturevolume 430, pages174–180 (2004)Cite this article

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 lampreyVLR 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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Figure 1: Lamprey leukocytes and VLRs.
Figure 2: Diversity of VLRs from two lampreys.
Figure 3: Graphic representation of protein divergence among 112 VLR diversity regions PCR amplified from 13 individual lampreys.
Figure 4: Sea lamprey genome harbours a singleVLR locus.
Figure 5: TheVLR locus.

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Acknowledgements

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.

Author information

Authors and Affiliations

  1. Division of Developmental and Clinical Immunology, University of Alabama at Birmingham, Birmingham, Alabama, 35294, USA

    Zeev Pancer, Götz R. A. Ehrhardt, G. Larry Gartland & Max D. Cooper

  2. Departments of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, 35294, USA

    Zeev Pancer & Max D. Cooper

  3. Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, 35294, USA

    Max D. Cooper

  4. Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, 35294, USA

    G. Larry Gartland & Max D. Cooper

  5. Howard Hughes Medical Institute, University of Alabama at Birmingham, Birmingham, Alabama, 35294, USA

    Götz R. A. Ehrhardt & Max D. Cooper

  6. Molecular Genetics Program, Benaroya Research Institute at Virginia Mason, Seattle, Washington, 98101, USA

    Chris T. Amemiya

  7. University of Michigan, Ann Arbor, Michigan, 48109, USA

    Jill Ceitlin

Authors
  1. Zeev Pancer
  2. Chris T. Amemiya
  3. Götz R. A. Ehrhardt
  4. Jill Ceitlin
  5. G. Larry Gartland
  6. Max D. Cooper

Corresponding author

Correspondence toMax D. Cooper.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Supplementary Figure 1

Multiple alignment of 22 predicted VLR proteins from EST clones. (DOC 3785 kb)

Supplementary Figure 2

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 thegermline VLR, and the position of the stalk domain and GPI cleavage site. (DOC 2209 kb)

Supplementary Figure 3

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)

Supplementary Table 1

PCR primers used in this study. Sequence and position of primers are provided for cDNA clone LyEST2913 (AY578059) and for the genomicVLR 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.Nature430, 174–180 (2004). https://doi.org/10.1038/nature02740

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