The proposed studies in lampreys build on the findings that both jawless (agnathans) and jawed (gnathostomes) vertebrates have prototypic T-like and B-like lymphocyte lineages, although the jawless vertebrates (lampreys and hagfish) generate variable lymphocyte receptors (VLR) for antigen recognition by recombinatorial conversion of incomplete germline VLR genes (VLRA, VLRB and VLRC) into fully assembled VLR genes using diverse leucine-rich-repeat (LRR) donor sequences. Analysis of the development, distribution and function of the lamprey VLRA and VLRC lymphocyte lineages suggest that the VLRA and VLRC lineages represent the agnathan T cell analogues of gnathostome ?/? and ?/? T cells with allorecognition responsibility. The serial multistep assembly of VLRC and VLRA genes coincides with expression of cytidine deaminase1 (CDA1) a thymus-equivalent gill region termed the thymoid, whereas VLRB and CDA2 expression occurs primarily in hematopoietic tissues. Surprisingly, three additional CDA1-like genes, the products of which have deaminase and mutagenic activity, have now been identified. The first specific aim is to define the multigene CDA1 family members in lampreys, determine their cellular expression patterns and elucidate the structure and functions of their protein products. Circumstantial evidence implies that the VLRA and VLRC receptors rely on associated transmembrane molecules for their cell surface expression and signaling competence. The second specific aim is therefore to determine the composite receptor structure and signaling competence for VLRA and VLRC. Pilot studies indicate that the VLRA+ and VLRC+ lymphocytes preferentially respond to allogeneic white blood cells. The third specific aim is to identify the antigens recognized by VLRA and VLRC receptors with the related goal of identifying lamprey histocompatibility antigens. Candidate histocompatibility genes will be examined for genetic polymorphism, expression patterns and immunostimulatory potential. A long term goal is to test the hypothesis that VLRA and VLRC recognize histocompatibility-associated antigens to achieve self versus non-self discrimination.
These studies in lampreys will yield insight into the basic evolutionary principles of the development and function of the two prototypic T cell arms of the adaptive immune system. A newly-discovered family of genes, some of which have hyper-mutagenic activity, will be extensively characterized.
| Das, Sabyasachi; Sutoh, Yoichi; Hirano, Masayuki et al. (2016) Characterization of Lamprey BAFF-like Gene: Evolutionary Implications. J Immunol 197:2695-703 |
| Han, Qifeng; Das, Sabyasachi; Hirano, Masayuki et al. (2015) Characterization of Lamprey IL-17 Family Members and Their Receptors. J Immunol 195:5440-51 |
| Das, Sabyasachi; Li, Jianxu; Hirano, Masayuki et al. (2015) Evolution of two prototypic T cell lineages. Cell Immunol 296:87-94 |
| Altman, Meghan O; Bennink, Jack R; Yewdell, Jonathan W et al. (2015) Lamprey VLRB response to influenza virus supports universal rules of immunogenicity and antigenicity. Elife 4: |
| Holland, Stephen J; Gao, Mingming; Hirano, Masayuki et al. (2014) Selection of the lamprey VLRC antigen receptor repertoire. Proc Natl Acad Sci U S A 111:14834-9 |
| Das, Sabyasachi; Li, Jianxu; Holland, Stephen J et al. (2014) Genomic donor cassette sharing during VLRA and VLRC assembly in jawless vertebrates. Proc Natl Acad Sci U S A 111:14828-33 |
| Das, Sabyasachi; Hirano, Masayuki; Aghaallaei, Narges et al. (2013) Organization of lamprey variable lymphocyte receptor C locus and repertoire development. Proc Natl Acad Sci U S A 110:6043-8 |
| Lada, Artem G; Stepchenkova, Elena I; Waisertreiger, Irina S R et al. (2013) Genome-wide mutation avalanches induced in diploid yeast cells by a base analog or an APOBEC deaminase. PLoS Genet 9:e1003736 |
| Li, Jianxu; Das, Sabyasachi; Herrin, Brantley R et al. (2013) Definition of a third VLR gene in hagfish. Proc Natl Acad Sci U S A 110:15013-8 |
| Smith, Jeramiah J; Kuraku, Shigehiro; Holt, Carson et al. (2013) Sequencing of the sea lamprey (Petromyzon marinus) genome provides insights into vertebrate evolution. Nat Genet 45:415-21, 421e1-2 |
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