The origins of vertebrate adaptive immunity

Abstract

Adaptive immunity is mediated through numerous genetic and cellular processes that generate favourable somatic variants of antigen-binding receptors under evolutionary selection pressure by pathogens and other factors. Advances in our understanding of immunity in mammals and other model organisms are revealing the underlying basis and complexity of this remarkable system. Although the evolution of adaptive immunity has been thought to occur by the acquisition of novel molecular capabilities, an increasing amount of information from new model systems suggest that co-option and redirection of pre-existing systems are the main source of innovation. We combine evidence from a wide range of organisms to obtain an integrated view of the origins and patterns of divergence in adaptive immunity.

Figure 1. Lymphocyte development and antigen receptor diversification in jawed vertebrates

A haematopoietic progenitor cell gives rise to distinct B and T cell lineages. Transcriptional networks (not depicted) are crucial for the differentiation and maintenance of cellular identity. Three unique processes — variable, diversity and joining region (V(D)J) recombination, somatic hypermutation and class-switch recombination — diversify antigen receptor genes. For clarity, some details are simplified or omitted. V (red boxes), D (green boxes) and J (dark blue boxes) segments for representative T cells (T cell receptor α-chain (TCRα) and TCRβ)) and B cells (immunoglobulin heavy chain (IgH) and immunoglobulin light chain (IgL)) are shown. The constant region for the Igμ isotype (Cμ) and a single representative downstream Cγ exon within the IgH locus are depicted. Key factors that facilitate each diversification step are shown in yellow ovals. During V(D)J recombination, recombination signal sequences (RSSs; blue and red triangles) direct the recombination-activating gene 1 (RAG1)–RAG2 recombinase complex to individual gene segments (red and blue boxes). The recombinase introduces two double-strand DNA breaks with blunt signal ends and hairpin-sealed coding ends. In the subsequent joining phase, terminal deoxynucleotidyltransferase (TdT), a template-independent DNA polymerase, adds random nucleotides to the junction of the gene elements, thereby increasing repertoire diversity dramatically; the RSSs are joined without further end processing and form excision circles. Once functional DNA rearrangements occur, TCR sequences are unaltered. After encounter with antigen, B cells further recombine the receptor by somatic hypermutation and class-switch recombination. Somatic hypermutation is initiated by activation-induced cytidine deaminase (AID), which deaminates individual cytidines within the V(D)J exon of the immunoglobulin gene, leading to U:G mismatches (yellow star). Subsequent error-prone repair results in individual point mutations (yellow dot in the gene and yellow bar in the immunoglobulin molecules), and B cells with higher affinity for the original antigen are selected. During class-switch recombination, AID creates U:G mismatches in the highly repetitive switch (S) regions (blue and green ovals) that are upstream of the exons encoding the constant regions of different isotypes. Error-prone repair leads to the generation of double-strand DNA breaks, excision of the intervening DNA (containing the Cμ exons) and joining of the remains of the switch regions. The recombined, somatically mutated V(D)J region is then associated with Cγ (green box), instead of Cμ. The precise order in which somatic hypermutation and class-switch recombination occur is unclear. Class-switch recombination has occurred in almost all high-affinity immunoglobulin-expressing B cells. In the course of a humoral immune response, B cells undergo terminal differentiation into plasma cells, which secrete large amounts of soluble immunoglobulins. γδ T cells — in which γδ TCR genes, instead of their αβ TCR genes, have been rearranged — and immunoglobulin gene conversion, which has been demonstrated in differentiating B cells of birds and rabbits, are not shown.

Figure 2. Relationships among animal phyla and subphyla with direct bearing on the origins of V(D)J recombination in jawed vertebrates

Major groups from the deuterostome superphylum are shown (a small phylum Xenoturbellida is omitted). Recent genome sequences from each of these clades are rapidly increasing our understanding of the origins of jawed vertebrate adaptive immunity. Hemichordates have features of chordates, with which they were once placed, but now are classed as a sister group to the echinoderms. Yellow diamonds indicate placement of two forms of adaptive immunity in jawed and jawless vertebrates; yellow circles indicate clades with complex multigene families encoding innate immune receptors.

Figure 3. Evolutionary co-option of ancient biological systems into lymphocytes that express V(D)J receptors

The cumulative acquisition of jawed vertebrate lymphoid properties within the lineage from an invertebrate ancestor to a modern jawed vertebrate is illustrated. The deuterostome ancestor probably had a complex form of innate immunity and the capacity to carry out unrelated, general cellular processes that are integral to modern jawed vertebrate immune cell (lymphocyte) function. The precursor immunocyte represents a collection of features inferred from genome sequence analyses and functional biochemistry of invertebrate deuterostomes, including a single homologue (polymerase-μ–TdT) that possesses features of both TdT (terminal deoxynucleotidyl transferase) and polymerase-μ (a related enzyme). The proposed early V(D)J receptor lymphocyte is based on observations in both jawed and jawless vertebrate lymphocytes, although jawless vertebrates use variable lymphocyte receptors (VLRs), as well as unrelated mechanisms of immune receptor diversification and membrane anchoring. A role has been proposed for activation-induced cytidine deaminase (AID)-related molecules in the generation of VLR diversity in lampreys; however, the relationship to AID-based somatic hypermutation and class-switch recombination in jawed vertebrate V(D)J receptor systems has not been resolved. Some aspects of the diversification of early lymphocytes into B cell- and T cell-like type cells may be a general feature of both jawed and jawless vertebrates or reflect convergent evolution. At this stage in the evolution of jawed vertebrate adaptive immunity, a genetic event that disrupted a V-type immunoglobulin domain formed a site for genetic recombination and subsequent receptor diversification. The characteristics of the jawed vertebrate V(D)J receptor lymphocyte represent the main cellular and structural features that are widespread among various taxonomic groups. Diversification of lymphocyte form and function reflects a complex integration of diverse biological features.