Both jawless vertebrates, such as lampreys and hagfish, and jawed vertebrates (encompassing species as diverse as sharks and humans) possess T-like and B-like lymphocytes.
Jawless vertebrates use variable lymphocyte receptors (VLRs) consisting of leucine-rich repeats whereas jawed vertebrates rely on antigen receptors of the immunoglobulin superfamily, such as immunoglobulins and T cell receptors (TCRs).
All vertebrates use somatic diversification to generate highly diverse repertoires of antigen receptors. Jawless vertebrates diversify their VLR genes by a process akin to gene conversion, whereas the diversification of immunoglobulin and TCR genes is achieved by the process of V(D)J recombination.
T-like cells develop in the thymoids of lampreys and the thymus of jawed vertebrates, whereas B cells develop in anatomically distinct haematopoietic tissues.
The astounding sequence diversity of the VLRA receptors expressed by T-like cells of lampreys suggests that mechanisms exist to tame potential self-reactivity; the search for an MHC equivalent is one of the priorities in the study of cellular immunity in jawless vertebrates.
Both jawless vertebrates, such as lampreys and hagfish, and jawed vertebrates (encompassing species as diverse as sharks and humans) have an adaptive immune system that is based on somatically diversified and clonally expressed antigen receptors. Although the molecular nature of the antigen receptors and the mechanisms of their assembly are different, recent findings suggest that the general design principles underlying the two adaptive immune systems are surprisingly similar. The identification of such commonalities promises to further our understanding of the mammalian immune system and to inspire the development of new strategies for medical interventions targeting the consequences of faulty immune functions.
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I apologize to all of my colleagues whose work could not be cited directly, owing to space constraints. I thank members of my group for their contributions and insightful discussions and T. Manke for help with the preparation of the figure shown in Supplementary information S2. This work was supported by grants from the Max Planck Society, the European Union and the Deutsche Forschungsgemeinschaft.
The author declares no competing financial interests.
- Variable lymphocyte receptors
(VLRs). Alternative forms of somatically diversified antigen receptors expressed by lymphocytes of jawless vertebrates. The combinatorial diversity of VLRs is based on variable numbers of leucine-rich repeat elements assembled by a gene conversion process.
- 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.
- Proto-adaptive immune systems
Immune systems of invertebrates that have many of the characteristics of the adaptive immune systems of vertebrates, such as selective expression of individual members of immune receptor gene families and limited somatic diversification.
- B1 and B2 cells
B1 cells are the minority population of B cells. These cells express CD5, respond quickly to antigen, produce antibodies of broad specificity and do not depend on MHC class II-mediated T cell help.B2 cells are the main population of B cells. These cells do not express CD5, respond more slowly to antigen than B1 cells, produce antibodies of narrow specificity and depend on MHC class II-mediated T cell help.
A group of jawed vertebrates to which most living bony fish belong. Popular model species are Danio rerio (zebrafish) and Oryzias latipes (medaka).
- Natural killer cells
Lymphocytes that confer innate immunity. They were originally defined on the basis of their cytolytic activity against tumour targets, but it is now recognized that they serve a broader role in host defence against invading pathogens.
- Whole-genome duplication
The duplication of an entire genome is considered to have a major role in evolution, because it generates paralogues of each gene that can then assume new functions.
A hypothetical ancestral lymphocyte of invertebrates from which the functionally distinct lymphocyte lineages of vertebrates have evolved.
An animal superphylum composed of four phyla: the chordates (which include vertebrates), the echinoderms (consisting of starfish, sea urchins and allied species), the hemichordates (acorn worms) and Xenoturbellida (containing two marine worm-like species).
- V(D)J recombination
Somatic rearrangement of variable (V), diversity (D) and joining (J) regions of the genes that encode antigen receptors, leading to repertoire diversity of both B cell and T cell receptors.
- Recombination activating gene
(RAG). A protein involved in creating the double strand DNA breaks necessary for producing the rearranged gene segments that encode the complete protein chains of B cell and T cell receptors.
- Translocon configuration
An antigen receptor gene structure in which many variable, diversity and joining elements occur together with one single constant region element.
- Combinatorial diversity
A form of sequence variation that occurs when one each of many genetic elements, for example variable and joining elements, are fused together during the process of somatic rearrangement of antigen receptor genes. This is an important source of sequence variability in all antigen receptors of vertebrates.
- Junctional diversity
A form of sequence variation that occurs when different genetic elements, for example variable and joining elements, are fused together by an error-prone DNA repair mechanism, such as non-homologous end joining. This is one of the sources of diversity generated by V(D)J recombination, the other being combinatorial diversity.
- Allelic exclusion
In theory, every B cell has the potential to produce two immunoglobulin heavy chains and two immunoglobulin light chains. In practice, however, a B cell produces only one immunoglobulin heavy chain and most produce only one immunoglobulin light chain. Similarly, most T cells produce only a single TCRβ protein. The process by which the production of two different chains is prevented is known as allelic exclusion. Allelic exclusion is accomplished primarily through regulated V(D)J recombination.
A transmembrane receptor involved in the pathway for direct cell–cell signalling through its association with a transmembrane ligand of the Delta or Serrate (jagged) family on a neighbouring cell. The large intracellular domain of Notch is cleaved and travels to the nucleus to become a direct co-activator of the transcription factor RBPJ (also known as CSL).
The process of responding to antigens that are distinct between members of the same species, such as MHC molecules or blood group antigens.
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Boehm, T. Design principles of adaptive immune systems. Nat Rev Immunol 11, 307–317 (2011). https://doi.org/10.1038/nri2944
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