VLR-based adaptive immunity

Abstract

Lampreys and hagfish are primitive jawless vertebrates capable of mounting specific immune responses. Lampreys possess different types of lymphocytes, akin to T and B cells of jawed vertebrates, that clonally express somatically diversified antigen receptors termed variable lymphocyte receptors (VLRs), which are composed of tandem arrays of leucine-rich repeats. The VLRs appear to be diversified by a gene conversion mechanism involving lineage-specific cytosine deaminases. VLRA is expressed on the surface of T-like lymphocytes; B-like lymphocytes express and secrete VLRB as a multivalent protein. VLRC is expressed by a distinct lymphocyte lineage. VLRA-expressing cells appear to develop in a thymus-like tissue at the tip of gill filaments, and VLRB-expressing cells develop in hematopoietic tissues. Reciprocal expression patterns of evolutionarily conserved interleukins and chemokines possibly underlie cell-cell interactions during an immune response. The discovery of VLRs in agnathans illuminates the origins of adaptive immunity in early vertebrates.

Figure 1

Organization and assembly of VLR genes. (a) Assembly of VLR genes. Multiple LRRNT-, LRR1-, LRRV-, LRRVe-, CP-, and LRRCT-encoding modules are located adjacent to the germ-line VLR gene. During the development of lymphoid cells, these modules are incorporated into the VLR gene by a gene conversion–like mechanism. The assembled VLR gene encodes a GPI-anchored or transmembrane protein. LRR1 and LRRVe denote LRRV modules located at the N and C termini, respectively. The figure is intended to emphasize the essential features of VLR assembly and does not reproduce the organization of a specific VLR locus. (b) Comparison of the germ-line structures of known VLR genes. The organization of the VLR gene shows minor variations depending on loci and species. (Abbreviations: CP, connecting peptide; CT, C terminal; GPI, glycosyl-phosphatidylinositol; LRR, leucine-rich repeat; NT, N terminal; VLR, variable lymphocyte receptor.)

Figure 2

Three-dimensional structures of variable lymphocyte receptor (VLR) molecules. Crystal structures of lamprey VLRA (PDB ID 3M18) and VLRB (PDB ID 3E6J) molecules and a predicted three-dimensional structure of lamprey VLRC (accession number BAJ14926). Prediction was made using the crystal structure of lamprey VLRB as a template. Protrusions located in the C-terminal leucine-rich repeat (LRRCT) of VLRA and VLRB are indicated by gray arrowheads.

Figure 3

The thymoid structure at the tip of gill filaments of lamprey larvae. (a) Lympho-epithelial structures at the tip of gill filaments as revealed by light microscopy after fixation in Bouin’s solution and hematoxylin/eosin (H&E) staining. The blood vessel (BV) underneath the thymoid is indicated; secondary lamellae emanate from the filament stem. The so-called cavernous bodies (CB) are located at the base of the gill filaments. (b) RNA in situ hybridization after fixation in paraformaldehyde with a CDA1-specific probe reveals the presence of developing T-like cells in the lymphoepithelial tissues at the tip of the gill filaments.

Figure 4

Evolution of adaptive immunity in vertebrates. A common ancestor of jawed and jawless vertebrates is hypothesized to have possessed primordial versions of BCR/TCR and VLR. Bifurcation of lymphocytes also seems to have taken place in the vertebrate ancestor. Acquisition of RAG recombinase activities likely occurred after the emergence of cytosine deaminase activities; this event together with a second round of WGD appear to have played a crucial role in the emergence of the jawed vertebrate-type adaptive immune system. After the split of jawless and jawed vertebrates, further diversification at the genetic and cellular levels occurred independently in these two groups of vertebrates. Cells of the T- and B-lymphocyte lineages are indicated in light green and orange, respectively. Abbreviations: BCR, B cell receptor; RAG, recombination-activating gene; TCR, T cell receptor; VLR, variable lymphocyte receptor; WGD, whole-genome duplication.