The invention of lymphocytes

Abstract

Lamprey and hagfish are surviving representatives of the most ancient vertebrates. They possess adaptive immune systems based on a vast, somatically diversified repertoire of lymphocyte-bound antigen receptors. Despite these similarities to antibody and T cell receptors (TCR) of later vertebrates, the variable lymphocyte receptors (VLR) are not related to the immunoglobulin (Ig)-superfamily of genes; and instead of V(D)J recombination VLR are somatically assembled by a gene conversion process. However, recent studies have revealed two lamprey lymphocyte subsets so closely resembling B cells and T cells that separate lymphocyte lineages must have already existed in the ancestral vertebrate, before Ig/TCR emergence. VLR and Ig/TCR arose independently, but the convergent evolution they display actually reflects their selection in cells with specialized functions.

Figure. 1

Adaptive immune features in vertebrates. The phylum Chordata includes jawed vertebrates (gnathostomes), jawless vertebrates (agnathans like hagfish and lamprey), and invertebrate chordates, such as cephalochordates (amphioxus) and urochordates (tunicates). Animals referred to in the text are indicated. The scale shows when taxa emerged in evolution. A much-debated issue is the phylogenetic position of lampreys, here depicted as sister group of jawed vertebrates [42]. The immune system features include hematopoietic cells and their key gene products that enable antigen recognition (cell surface receptors Ig, TCR, MHC class I, MHC class II) and generate antigen receptor sequence diversity (RAG1/RAG2, AID-APOBEC cytidine deaminase family). The immune systems of the jawed vertebrates are reviewed in ref. [43]. The agnathan characteristics are discussed in the text. The genomes of Ciona (tunicate) and amphioxus have been examined for immune components [44, 45]; it is not clear whether RAG2 exists in amphioxus.

Figure 2

Somatically recombined antigen receptors in vertebrates. Top. Immunoglobulin genes are shown in their germline configuration (VH, DH, JH gene segments for H chain, VL and JL gene segments for L chain) (right), rearranged as VDJ (H chain) and VJ (L chain) (center), transcribed with their constant regions (CH in H chain, CL in L chain) and expressed as integral membrane receptors on lymphocytes (right). Triangles indicate recombination signal sequences recognized by RAG. Bottom. The lamprey VLRB gene is shown in germline configuration (left), as assembled VLR with inserted LRR sequences (center), as a horseshoe-shaped receptor whose concave surface forms a ligand-binding β sheet (right) [36]. The germline gene (signal peptide, SP, gray oval; partial 5′LRRNT, yellow; 5′LRRCT, 3′LRRCT, blue; stalk and hydrophobic tail (HT)) and flanking cassettes with LRRNT-LRR1, LRRV, LRRCT, are drawn after ref. [5]; relative distances are not accurate. The successive transfer of LRR sequences is initiated from the 5′ and 3′ ends of the germline gene, culminating in the assembly of the mature VLR. This consists of signal peptide (gray oval), N-terminal LRR (LRRNT, yellow ellipse), LRR1 of 18 amino acids and additional LRRV modules of 24 amino acids (red hexagons), connecting peptide (CP, blue rectangle) of 13 amino acids, C-terminal LRR (LRRCT, in navy) varying in length, and the C terminus (stalk and hydrophobic tail (HT), black oval). The arrow at right points to the LRRCT insert (blue loop in receptor) when long enough to be a protrusion.