The traditional view is that innate immunity has a long phylogenetic history, whereas conventional adaptive immunity is restricted to jawed vertebrates. However, recent studies have shown that there might be alternative forms of adaptive immunity in jawless vertebrates and invertebrates and that diversified immune receptors are far more broadly distributed in phylogeny than was previously thought.
Mediators of adaptive and innate immunity use related mechanisms to diversify structural domains in immune receptors. Pathogens use similar methods of genetic change to diversify many of the same types of domain to evade host immune defences.
Various mechanisms are used to generate diversity in immune effector molecules. Depending on the level of phylogenetic development, different mechanisms or combinations of these mechanisms might be used to carry out these processes.
Lymphocyte-like cells are seen in jawless vertebrates despite the apparent absence of authentic B- and T-cell-receptor homologues in these species. A leucine-rich-repeat-encoding gene that undergoes rearrangement in single lymphocytes is a possible mediator of adaptive immunity in both extant groups of jawless vertebrates (lampreys and hagfish).
Natural killer (NK)-cell immunity seems to have a long phylogenetic history. Members of a family of authentic variable-region-containing activating and inhibitory type I transmembrane proteins that is found in bony fish share several properties with killer-cell immunoglobulin-like receptors (KIRs), which are the main family of diversified NK-cell receptors in humans.
The enormously complex conventional adaptive immune system, which uses segmental rearrangement of variable, diversity and joining elements, has been assembled during evolution by integrating molecules that are involved in unrelated aspects of cellular metabolism. Furthermore, many of these same molecules are used to effect other germline changes during the developmental maturation of single lymphocytes.
Both the innate and adaptive immune systems use an unexpectedly large number of different solutions in terms of receptor variation to solve the similar problem of host defence against infectious challenge.
Numerous studies of the mammalian immune system have begun to uncover profound interrelationships, as well as fundamental differences, between the adaptive and innate systems of immune recognition. Coincident with these investigations, the increasing experimental accessibility of non-mammalian jawed vertebrates, jawless vertebrates, protochordates and invertebrates has provided intriguing new information regarding the likely patterns of emergence of immune-related molecules during metazoan phylogeny, as well as the evolution of alternative mechanisms for receptor diversification. Such findings blur traditional distinctions between adaptive and innate immunity and emphasize that, throughout evolution, the immune system has used a remarkably extensive variety of solutions to meet fundamentally similar requirements for host protection.
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We thank B. Pryor for editorial assistance. We also thank C. Amemiya, M. Cooper, S. Desai, Z. Pancer and J. Yoder for providing valuable comments regarding the subject matter of this Review, and M. Anderson, A. De Tomaso, D. Eason, S. Fugmann, R. Haire, J. Hernandez Prada, N. Miller, D. Ostrov, J. Rast and N. Schnitker for sharing unpublished results. M. Sexton assisted with the preliminary graphic design. G.W.L. is supported by grants from the National Institutes of Health (United States). L.J.D. is supported by a fellowship from the H. Lee Moffitt Cancer Center & Research Institute (United States).
The authors declare no competing financial interests.
All animals that are above the phylogenetic level of protozoans and sponges.
Movement of a segment of DNA from one position in the genome to another position (or to a different genome).
- GERMLINE DIVERSIFICATION
Changes in DNA sequence that occur in the germline of a species and are heritable.
- SOMATIC DIVERSIFICATION
Changes in DNA sequence that occur in individual cells and their progeny. Traditionally, this process has been associated with lymphocytes and is brought about during gene rearrangements, as well as through gene conversion and somatic hypermutation.
- JUNCTIONAL VARIATION
The introduction of genetic changes at the joining interfaces of rearranged variable (V), diversity (D) and joining (J) segmental elements in immunoglobulins and T-cell receptors.
- GENE CONVERSION
A homologous-recombination event in which the donor gene(s) remains unmodified and an acceptor gene acquires the recombined segment. In chickens, variable (V)-region pseudogenes are donors that modify the functional, rearranged V gene in bursal follicles, and this process generates a diverse pre-immune repertoire.
- CLASS-SWITCH RECOMBINATION
The process by which the heavy-chain class that is associated with a specific VDJ rearrangement is changed through recombination during B-cell ontogeny.
Reflecting characteristics that are acquired subsequent to divergence from a common ancestral form.
- HISTOCOMPATIBILITY REACTION
The reaction to, and/or rejection of, individual cells or tissues that are introduced from one individual to a genetically different individual.
- RECOMBINATION SIGNAL SEQUENCE
A conserved genetic element that constitutes a recognition site for the V(D)J recombinase proteins, which are encoded by the genes recombination-activating gene 1 (RAG1) and RAG2. These sites consist of a palindromic 7-base-pair sequence that is immediately adjacent to the coding gene segments — variable (V), diversity (D) or joining (J) — and is separated by a 12- or 23-base-pair spacer from a relatively conserved 9-base-pair sequence.
- NON-HOMOLOGOUS END JOINING
A generic mechanism for repair of double-stranded DNA breaks. It joins hairpin coding ends that form during V(D)J recombination.
- COMPLEMENTARITY-DETERMINING REGIONS
(CDRs). The most variable parts of immunoglobulin and the T-cell receptor. These form loops that make contact with specific ligands. There are three such regions (CDR1, CDR2 and CDR3) in each variable domain.
- ALLELIC EXCLUSION
A mechanism by which antigen receptors of a single specificity are expressed at the cell surface of a lymphocyte. This is an integral step in the clonal commitment of a cell lineage.
- TYPE I TRANSMEMBRANE PROTEIN
An integral membrane protein that is composed of an amino-terminal extracellular region, a transmembrane domain and a carboxy-terminal intracellular region (for example, T-cell receptors).
- TYPE II TRANSMEMBRANE PROTEIN
An integral membrane protein that is composed of an amino-terminal intracellular region, a transmembrane domain and a carboxy-terminal extracellular region (for example, Ly49).
- IMMUNORECEPTOR TYROSINE-BASED INHIBITORY MOTIF
(ITIM). A structural motif that contains tyrosine residues and is found in the cytoplasmic tails of several inhibitory receptors, such as the low-affinity Fc receptor for IgG FcγRIIB and paired immunoglobulin-like receptor B (PIRB). The prototype six-amino-acid ITIM sequence is (I/V/L/S)XYXX(L/V), where X denotes any amino acid. Ligand-induced clustering of these inhibitory receptors results in tyrosine phosphorylation, often by SRC-family protein tyrosine kinases, and this provides a docking site for the recruitment of cytoplasmic phosphatases that have a SRC homology 2 (SH2) domain.
- IMMUNORECEPTOR TYROSINE-BASED ACTIVATION MOTIF
(ITAM). B-cell, T-cell and natural-killer-cell receptors are non-covalently associated with transmembrane proteins that contain one or more ITAMs. The amino-acid sequence of an ITAM is (D/E)XXYXX(L/I)X6–8YXX(L/I), where X denotes any amino acid. This is tyrosine phosphorylated after engagement of the ligand-binding subunits, which triggers a cascade of intracellular events that results in cellular activation.
- IMMUNORECEPTOR TYROSINE-BASED SWITCH MOTIF
(ITSM). This motif has the amino-acid sequence TXYXX(V/I), where X denotes any amino acid. It recruits many of the same signalling molecules as do immunoreceptor tyrosine-based inhibitory motifs (ITIMs) and immunoreceptor tyrosine-based activation motifs (ITAMs), but it also recruits SAP (signalling lymphocytic activation molecule (SLAM)-associated protein).
Similar sequences that are found in different species and can be attributed to descent from a common ancestral sequence.
The same order of genes occurring on chromosomes that are present in different organisms.
- BIRTH AND DEATH
In the context of multigene families encoding immune molecules, this involves the creation and extinction of alleles, and it is co-driven by pathogen load during evolution.
A soluble protein that occurs naturally or in response to immunization and agglutinates a particulate antigen. The term can be applied to an immunoglobulin molecule or to proteins that are unrelated to immunoglobulins.
- EXPRESSED SEQUENCE TAG
(EST). A genetic sequence that corresponds to an mRNA or a region of an mRNA.
- LEUCINE-RICH REPEAT
(LRR). Domains that contain LRRs have a conserved solenoid structure, typically of 20–29 residues and containing an 11 amino-acid consensus sequence, LXXLXLXX(N/C)XL, where X denotes any amino acid. These domains lack considerable identity or similarity in the amino acids surrounding this structure, both between and among families. Sequence substitutions in LRR-containing proteins are associated with changes in specificity and relative affinity towards specific determinants.
Reflecting the shared characteristic(s) of a common ancestral form.
A member of the subphylum Cephalochordata. In this Review, cephalochordates are represented by amphioxus, which has a notochord, dorsal nerve cord and pharyngeal gills that are well developed in the adult stage.
- SECRETION SIGNAL-PEPTIDE SELECTION
A cloning method that is based on the rescue of ampicillin resistance in a vector that encodes a defective β-lactamase, by the substitution of an exogenous leader, as well as additional coding sequence, from transmembrane or secreted proteins.
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Litman, G., Cannon, J. & Dishaw, L. Reconstructing immune phylogeny: new perspectives. Nat Rev Immunol 5, 866–879 (2005). https://doi.org/10.1038/nri1712
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