The adaptive immune system arose 500 million years ago in ectothermic (cold-blooded) vertebrates. Classically, the adaptive immune system has been defined by the presence of lymphocytes expressing recombination-activating gene (RAG)-dependent antigen receptors and the MHC. These features are found in all jawed vertebrates, including cartilaginous and bony fish, amphibians and reptiles and are most likely also found in the oldest class of jawed vertebrates, the extinct placoderms. However, with the discovery of an adaptive immune system in jawless fish based on an entirely different set of antigen receptors — the variable lymphocyte receptors — the divergence of T and B cells, and perhaps innate-like lymphocytes, goes back to the origin of all vertebrates. This Review explores how recent developments in comparative immunology have furthered our understanding of the origins and function of the adaptive immune system.
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The authors thank L. Du Pasquier and H. Matz for critical reading. M.F.F. has been supported by US National Institutes of Health (NIH) grants R01OD049 and RO1AI027877.
The author declares no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
- Bursa of Fabricius
An organ derived from a cloacal outpocketing in birds in which B cells develop.
Embryonically, animals in which the blastopore becomes the anus, including all of the vertebrates. Lower deuterostomes such as tunicates, lancelets and echinoderms are descendants of ancestors before the emergence of adaptive immunity and the genome-wide duplications that occurred early in vertebrate history.
Jawed vertebrates, including placoderms, cartilaginous fish, bony fish, amphibians, reptiles, birds and mammals.
- Evolutionary ‘Big Bang’
The rapid emergence of the majority of molecules, mechanisms and tissues that define human adaptive immunity, which most likely occurred in placoderms (see Fig. 2).
- Variable lymphocyte receptors
(VLRs). Antigen receptors (VLRA and VLRB) found in the agnathan jawless fish (lamprey and hagfish).
- Follicular dendritic cells
(FDCs). Cells found in only warm-blooded vertebrates that present native antigen to B cells in the follicles and germinal centres of secondary lymphoid organs.
- Immunoglobulin superfamily
A family containing proteins with a specific immunoglobulin superfamily (IgSF) domain, including molecules such as immunoglobulins, T cell receptors and MHC class I and MHC class II molecules, in which there are unique members of the superfamily (VJ and C1 domains).
The most ancient extant vertebrates (lamprey and hagfish), which lack jaws.
A genus of aquatic amphibians that is a widespread model for basic science research, including in comparative immunology.
Vertebrates that serve as a tractable model for the transition from fish to tetrapods and share features with both groups.
Vertebrates with lobed fins, once thought to be extinct, that serve as a model for the transition from fish to tetrapods.
- ‘Dead end’ H chain immunoglobulin isotypes
Immunoglobulin heavy (H) chain isotypes that arose in particular vertebrate taxa but are apparently not perpetuated throughout the vertebrate tree.
- Somatic hypermutation
(SHM). A process that introduces activation-induced cytidine deaminase (AID)-initiating mutations into the immunoglobulin variable region genes of B cells during an adaptive immune response.
- Complementarity determining regions
(CDRs). Loops on one face of variable immunoglobulin superfamily domains in regions of both immunoglobulins and T cell receptors that contact antigen (or antigenic peptide–MHC complexes) and that display the greatest variability.
A complementarity determining region (CDR) that is generally considered to be the most diverse part of the immunoglobulin and T cell receptor binding site and is derived from recombination-activating gene (RAG)-mediated rearrangements during lymphocyte ontogeny.
- RAG transposon
A hypothetical transposable element that contains insertion elements, recombination signal sequences and (at least) one gene encoding the V(D)J recombination-activating protein 1 (RAG1) catalytic core, which invaded an immunoglobulin superfamily gene, initiating the generation of diversity in antigen receptor genes.
- Switch boxes
Repetitive DNA elements upstream of every immunoglobulin H (IgH) isotype gene in mammals that are involved in class switch recombination.
- APOBEC family
A specialized family of cytidine deaminases (CDAs) of which the best studied is activation-induced cytidine deaminase (AID), including its function in somatic hypermutation and class switch recombination. Members found in jawless fish (CDA1 and CDA2) are implicated in the rearrangement of the variable lymphocyte receptor genes, and other APOBEC family members in mammals are involved in viral defence and genome preservation.
- Copy choice
The gene conversion-like mechanism by which diversity is generated for the variable lymphocyte receptor genes in developing agnathan T and B cells.
The evolutionarily oldest nonclassical (MHC class Ib) molecule that presents lipid antigens to natural killer T cells and a subset of γδ T cells.
- NK gene complex
(NKC). A large family of C-type lectin genes in mammals involved primarily in natural killer (NK) cell recognition (for example, killer cell lectin-like receptor subfamily K member 1 (KLRK1) and CD94).
- Leukocyte immunoglobulin-like receptor complex
(LRC). A large family of immunoglobulin superfamily genes in mammals (found on chromosome 19 in humans) involved in many immune reactions, including natural killer cell receptors.
- Proteasome subunit-β type 11
(PSMβ11). Also known as B5T; an immunoproteasome catalytic subunit expressed specifically by the thymic cortical epithelium in all gnathostomes that is vital for the production of peptides involved in the positive selection of CD8+ T cells (cytotoxic T cells).
- Autoimmune regulator
(AIRE). A protein that is expressed specifically by the thymic medullary epithelium in all gnathostomes and is vital for central tolerance of T cells via the expression of tissue-specific antigens.
- Peanut agglutinin staining
A process that makes use of lectin, which recognizes de-sialylated glycoproteins, most conspicuously staining germinal centre B cells, double-positive thymocytes and dendritic cell subsets.
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Flajnik, M.F. A cold-blooded view of adaptive immunity. Nat Rev Immunol 18, 438–453 (2018). https://doi.org/10.1038/s41577-018-0003-9
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