Organization of lamprey variable lymphocyte receptor C locus and repertoire development

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Jawless vertebrates (cyclostomes) have an alternative adaptive immune system in which lymphocytes somatically diversify their variable lymphocyte receptors (VLR) through recombinatorial use of leucine-rich repeat cassettes during VLR gene assembly. Three types of these anticipatory receptors in lampreys (VLRA, VLRB, and VLRC) are expressed by separate lymphocyte lineages. However, only two VLR genes (VLRA and VLRB) have been found in hagfish.Here we have identified a third hagfish VLR, which undergoes somatic assembly to generate sufficient diversity to encode a large repertoire of anticipatory receptors. Sequence analysis, structural comparison, and phylogenetic analysis indicate that the unique hagfish VLR is the counterpart of lamprey VLRA and the previously identified hagfish "VLRA" is the lamprey VLRC counterpart. The demonstration of three orthologous VLR genes in both lampreys and hagfish suggests that this anticipatory receptor system evolved in a common ancestor of the two cyclostome lineages around 480 Mya.adaptive immunity | molecular evolution | antigen receptor | agnatha

mentioning

confidence: 99%

Definition of a thirdVLRgene in hagfish

Das

Herrin

et al. 2013

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“…Previous work has identified in lamprey larvae a thymus equivalent (referred to as the thymoid), situated at the tips of the gill filaments; this lymphoepithelial tissue is characterized by the expression of genes such as FOXN1 and DLL4 that are also found in the thymopoietic tissues of jawed vertebrates (18). These findings, together with the observations of a high frequency of incomplete and nonfunctional VLRA (18) and VLRC (6,19) assemblies and the expression of the CDA1 gene (18), indicate that VLRA and VLRC receptor genes are assembled in this tissue.…”

mentioning

confidence: 70%

“…This insert, whose secondary structure also varies, is critical for recognition of protein and carbohydrate antigens (14,15,(22)(23)(24)(25). The average length of the LRRCT insert in VLRCs (2 residues) is much less than in VLRAs (10 residues) or VLRBs (8 residues), and sequence variation in the LRRCT module of VLRCs is substantially lower than in LRRCT of the other two VLR types (19,29). In the VLRC.1MP structure, the LRRCT insert comprises only 2 residues and does not protrude from LRRCT or extend across the concave surface of the VLR.…”

Section: Resultsmentioning

confidence: 99%

Selection of the lamprey VLRC antigen receptor repertoire

Holland

Gao

Hirano

et al. 2014

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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.adaptive immunity | molecular evolution | agnathans

“…The three VLR isotypes are differentially expressed by three distinct populations of lymphocytes in lampreys (9,13). The two types of T-like cells of lamprey, VLRA + and VLRC + lymphocytes, are generated in the thymoid, a lymphoepithelial tissue equivalent to the thymus (13)(14)(15); this situation is analogous to the development in the thymus of the two distinct αβ and γδ T-cell lineages in jawed vertebrates. The VLRB + cells appear to be generated in hematopoietic tissues outside of the thymoid (14), much like B cells in jawed vertebrates.…”

mentioning

confidence: 94%

“…The germ-line VLRC gene in lampreys is flanked by five types of donor LRR-encoding cassettes, which contribute to the assembly of mature VLRC genes in a stepwise manner ( Fig. 1 A and B): 3′ LRRNT-5′ LRR1 cassettes, 3′ LRR1-5′ LRRV cassettes, 3′ LRRV-5′ LRRV cassettes, 3′ LRRVt-CP-5′ LRRCT cassettes, and LRRCT cassettes (15). In an assessment of genomic donor cassettes contributing to the assembly of mature VLRA, VLRB, and VLRC genes, we found that four types of the genomic donor cassettes (3′ LRRNT-5′ LRR1, 3′ LRR1-5′ LRRV, 3′ LRRV-5′ LRRV, and 3′ LRRVt-CP-5′ LRRCT) may be shared in the assembly of the VLRA and VLRC genes (Fig.…”

Section: Figs S2-s4)mentioning

confidence: 99%

Genomic donor cassette sharing duringVLRAandVLRCassembly in jawless vertebrates

Das

Holland

et al. 2014

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Lampreys possess two T-like lymphocyte lineages that express either variable lymphocyte receptor (VLR) A or VLRC antigen receptors. VLRA + and VLRC + lymphocytes share many similarities with the two principal T-cell lineages of jawed vertebrates expressing the αβ and γδ T-cell receptors (TCRs). During the assembly of VLR genes, several types of genomic cassettes are inserted, in step-wise fashion, into incomplete germ-line genes to generate the mature forms of antigen receptor genes. Unexpectedly, the structurally variable components of VLRA and VLRC receptors often possess partially identical sequences; this phenomenon of module sharing between these two VLR isotypes occurs in both lampreys and hagfishes. By contrast, VLRA and VLRC molecules typically do not share their building blocks with the structurally analogous VLRB receptors that are expressed by Blike lymphocytes. Our studies reveal that VLRA and VLRC germ-line genes are situated in close proximity to each other in the lamprey genome and indicate the interspersed arrangement of isotype-specific and shared genomic donor cassettes; these features may facilitate the shared cassette use. The genomic structure of the VLRA/ VLRC locus in lampreys is reminiscent of the interspersed nature of the TCRA/TCRD locus in jawed vertebrates that also allows the sharing of some variable gene segments during the recombinatorial assembly of TCR genes.adaptive immunity | molecular evolution | selection | agnatha