Evolutionary implications of a third lymphocyte lineage in lampreys


Jawed vertebrates (gnathostomes) and jawless vertebrates (cyclostomes) have different adaptive immune systems1,2. Gnathostomes use T- and B-cell antigen receptors belonging to the immunoglobulin superfamily3,4. Cyclostomes, the lampreys and hagfish, instead use leucine-rich repeat proteins to construct variable lymphocyte receptors (VLRs), two types of which, VLRA and VLRB, are reciprocally expressed by lymphocytes resembling gnathostome T and B cells5,6,7. Here we define another lineage of T-cell-like lymphocytes that express the recently identified VLRC receptors8,9. Both VLRC+ and VLRA+ lymphocytes express orthologues of genes that gnathostome γδ and αβ T cells use for their differentiation, undergo VLRC and VLRA assembly and repertoire diversification in the ‘thymoid’ gill region, and express their VLRs solely as cell-surface proteins. Our findings suggest that the genetic programmes for two primordial T-cell lineages and a prototypic B-cell lineage were already present in the last common vertebrate ancestor approximately 500 million years ago. We propose that functional specialization of distinct T-cell-like lineages was an ancient feature of a primordial immune system.

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Figure 1: Tissue distribution of VLRA+, VLRB+ and VLRC+ lymphocytes.
Figure 2: Antigen and mitogen responses.
Figure 3: Gene-expression profiles of VLRA+, VLRB+ and VLRC+ lymphocytes and their poly(I:C) responses.
Figure 4: Analysis of VLRC, VLRA and VLRB transcription and assembly.

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Data deposits

Sequence data have been deposited in GenBank/EMBL/DDBJ databases under accession numbers KF385949KF385955.


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We thank C. L. Turnbough Jr for providing B. anthracis exosporium, H. Yi for help with electron microscopy, S. A. Durham and R. E. Karaffa II for help with cell sorting, S. Holland for help with gene orthology analysis, Q. Han for help with cloning, and B. R. Herrin, M. Kasahara and Y. Sutoh for suggestions and discussion. M.H., P.G., N.M., S.D. and M.D.C. are supported by National Institutes of Health grants (R01AI072435 and R01GM100151) and the Georgia Research Alliance; M.S. and T.B. are supported by the Max Planck Society.

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M.H., P.G., N.M., M.S., S.D., T.B. and M.D.C. designed the research, analysed data and wrote the paper; M.H., P.G., N.M., M.S., S.D. and T.B. carried out the research.

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Correspondence to Max D. Cooper.

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The authors declare no competing financial interests.

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Hirano, M., Guo, P., McCurley, N. et al. Evolutionary implications of a third lymphocyte lineage in lampreys. Nature 501, 435–438 (2013). https://doi.org/10.1038/nature12467

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