Review
doi: 10.1038/s41577-018-0003-9.A cold-blooded view of adaptive immunity
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- PMID:29556016
- PMCID: PMC6084782
- DOI: 10.1038/s41577-018-0003-9
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Review
A cold-blooded view of adaptive immunity
Martin F Flajnik. Nat Rev Immunol.2018 Jul.
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Abstract
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.
Conflict of interest statement
Competing interests
The author declares no competing interests.
Figures
Numbers to the left indicate the approximate number of years (millions of years ago (Myr ago)) since the emergence of the ancestor of each vertebrate class. The term ‘archaic mammals’ refers to how different reptilian ancestors gave rise to birds and mammals, and the most ancient mammals most likely had these features. Note that while birds clearly have germinal centres, they have lost many features of adaptive immunity and are deserving of an entire review article of their own to explain their unique immune system. Animals discussed in this Review include amphibians(Xenopus and axolotl), bony fish (trout, salmon, medaka, zebrafish, cod, Antarctic fish, coelacanths and lungfish), cartilaginous fish (nurse shark, skate and/or ray and elephant shark) and jawless fish (lamprey and hagfish). ?, unknown; CSR, class switch recombination; DCs, dendritic cells; FDCs, follicular dendritic cells; IgVH, immunoglobulin heavy chain variable region; SHM, somatic hypermutation; TCRδ, T cell receptor δ chain.
Immune features of each ectothermic vertebrate class, both in terms of leaps forward in evolution and unique characteristics of each group, are shown below the representative animal. Note that there appears to have been two Big Bangs, one at the emergence of the jawless fish and another when the gnathostomes emerged. In this and other figures, it has been assumed that the extinct placoderms had all the immune features of the cartilaginous fish, but this is speculative. AID, activation-induced cytidine deaminase; APOBEC, apolipoprotein B mRNA editing enzyme catalytic polypeptide-like; AIRE, autoimmune regulator; CDA, cytidine deaminase; CSR, class switch recombination; Ig, immunoglobulin; NKp30, natural killer cell p30-related protein; PSMβ11, proteasome subunit-β type 11; RAG, recombination-activating gene; SHM, somatic hypermutation; TAP, transporter associated with antigen processing; TAPL, TAP-like; TPN, tapasin; VLR, variable lymphocyte receptor.
The figure illustrates the main features of the antibodies found in amphibians, bony fish and cartilaginous fish and the variable lymphocyte receptors (VLRs) found in agnathans (jawless fish). Key differences in the variable (V), diversity (D), joining (J) and constant (C) domains of antibodies in each class are shown, as well as the structure of the leucine-rich repeat (LRR) cassettes found in agnathan VLRs. Note that naive B cells in the jawless fish also express cell surface VLRB in a monomeric form. The features noted below each molecule are described in the text and to some extent in FIG. 6. APOBEC, apolipoprotein B mRNA editing enzyme catalytic polypeptide-like; CT-LRR, carboxy-terminal LRR; GPI, glycosyl phosphatidylinositol; H, heavy; Ig, immunoglobulin; L, light; NAR, new antigen receptor; NT-LRR, amino-terminal LRR; TM, transmembrane.
The proto-MHC is shown at the top of the figure with several framework genes in blue found in all the MHC paralogous regions,. The immune genes in blue are inferred to be part of the ancestral MHC, and genes with asterisks (*) are proposed to have existed. Chromosomes 1, 6, 9 and 19 are the MHC paralogous regions (numbering is based on human chromosomes, but all vertebrates have such paralogous regions) arising as a consequence of the two rounds (R) of genome-wide duplications (1 R and 2 R in the figure); these two rounds of genome duplications are shown, with short descriptions of what is special for each paralogous syntenic group. Features of the MHC of each vertebrate class are shown beneath the representative animal from each class. α2m, α2 macroglobulin; β2m, β2 microglobulin; BRD, bromodomain protein; C3, complement component C3; IgSF, immunoglobulin superfamily; JAK, Janus kinase; NKR, natural killer receptor; NKR-C-type lectin, natural killer receptor of the C-type lectin family; NKR-IgSF, natural killer receptor of the IgSF; NOTCH, neurogenic locus Notch homologue protein; PBR, peptide-binding region; PSMβ8, proteasome subunit-β type 8; RXR, retinoid X receptor; TAP, transporter associated with antigen processing; TNFSF, tumour necrosis factor superfamily; TPN, tapasin.
It is proposed that a single population of conventional, haematopoietically derived dendritic cells (DCs) presents antigen to both T and B cells in ectotherms. This was likely the ancestral state before the appearance of follicular dendritic cells (FDCs) in mammals. Double-duty antigenpresenting cells (APCs) express MHC class II molecules, Fc receptors (FcRs) and complement receptors. BCR, B cell receptor.
The figure illustrates the key features of adaptive mucosal immunity in mammals, amphibians and fish. The major mucosal immunoglobulin is indicated for each group, but IgM can also be transported across mucosal epithelia, although its role is less important, where studied.?, unknown; CSR, class switch recombination; J chain, joining chain.aNasal organized lymphoid tissue is found in all amphibians examined exceptXenopus.bOrganized nasal tissue is lacking in the majority of bony fish (actinopterygians) but present in the lungfish (sarcopterygians).
References
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