Selection of the lamprey VLRC antigen receptor repertoire

• Type of Material: Article
• Authors: Stephen J. Holland, Max Planck Institute of Immunobiology and Epigenetics; Mingming Gao, University of Maryland; Masayuki Hirano, Emory University; Lakshminarayan M. Iyer, National Institutes of Health; Ming Luo, University of Maryland; Michael Schorpp, Max Planck Institute of Immunobiology and Epigenetics; Max Dale Cooper, Emory University; L. Aravind, National Institutes of Health; Roy A. Mariuzza, University of Maryland; Thomas Boehm, Max Planck Institute of Immunobiology and Epigenetics
• Language: English
• Date: 2014-10-14
• Publisher: National Academy of Sciences
• Publication Version: Final Published Version
• Copyright Statement: © 2014, National Academy of Sciences. All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1073/pnas.1415655111
• Title of Journal or Parent Work: Proceedings of the National Academy of Sciences
• ISSN: 0027-8424
• Volume: 111
• Issue: 41
• Start Page: 14834
• End Page: 14839
• Grant/Funding Information: M.L. was supported by the Joint Supervision PhD Project of the China Scholarship Council.; This work was supported by the Max Planck Society; and has received funding from the European Research Council (ERC) under the European Union's Seventh Framework Programme (FP7/2007-2013); ERC Grant Agreement ERC-2012-AdG–323126.; Work by L.M.I. and L.A. is funded by the Intramural Research Program of the NIH, Department of Health and Human Services; and that of M.D.C. and M.H. by NIH Grants AI072435 and GM100151.; R.A.M. was supported by National Institutes of Health (NIH) Grant AI036900.
• Keywords: Science & Technology - Other Topics; STRUCTURAL BASIS; SEA LAMPREY; adaptive immunity; MONOCLONAL-ANTIBODIES; DIVERSITY; Science & Technology; DIVERSIFICATION; EVOLUTION; Multidisciplinary Sciences; molecular evolution; ADAPTIVE IMMUNE-SYSTEM; VARIABLE LYMPHOCYTE RECEPTORS; HAGFISH; RECOGNITION; agnathans
• Research Categories: Health Sciences, Pathology; Health Sciences, Immunology

Abstract

The alternative adaptive immune system of jawless vertebrates is based on different isotypes of variable lymphocyte receptors (VLRs) that are composed of leucine-rich repeats (LRRs) and expressed by distinct B- and T-like lymphocyte lineages. VLRB is expressed by B-like cells, whereas VLRA and VLRC are expressed by two T-like lineages that develop in the thymoid, a thymus-like structure in lamprey larvae. In each case, stepwise combinatorial insertions of different types of short donor LRR cassettes into incomplete germ-line genes are required to generate functional VLR gene assemblies. It is unknown, however, whether the diverse repertoires of VLRs that are expressed by peripheral blood lymphocytes are shaped by selection after their assembly. Here, we identify signatures of selection in the peripheral repertoire of VLRC antigen receptors that are clonally expressed by one of the T-like cell types in lampreys. Selection strongly favors VLRC molecules containing four internal variable leucine-rich repeat (LRRV) modules, although VLRC assemblies encoding five internal modules are initially equally frequent. In addition to the length selection, VLRC molecules in VLRC⁺peripheral lymphocytes exhibit a distinct pattern of high entropy sites in the N-terminal LRR1 module, which is inserted next to the germ-line-encoded LRRNT module. This is evident in comparisons to VLRC gene assemblies found in the thymoid and to VLRC gene assemblies found in some VLRA⁺cells. Our findings are the first indication to our knowledge that selection operates on a VLR repertoire and provide a framework to establish the mechanism by which this selection occurs during development of the VLRC+ lymphocyte lineage.