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50 Million Years of Chordate Evolution: Seeking the Origins of Adaptive Immunity

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50 Million Years of Chordate Evolution: Seeking the Origins of Adaptive Immunity Commentary 50 million years of chordate evolution: Seeking the origins of adaptive immunity Diana J. Laird*†, Anthony W. De Tomaso*, Max D. Cooper‡, and Irving L. Weissman* *Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305-5324; and ‡Howard Hughes Medical Institute, University of Alabama, 378 Wallace Tumor Institute, Birmingham, AL 35294 gnathans, the most primitive chor- ertoire of antigenic shapes the universe sup- to situate this finding from the laboratory of Adates, are poised at a fascinating point plies (2). We would expect that living ag- Jan Klein within the field of evolutionary in evolution. In the 50 million years between nathans, hagfish and lamprey, might retain immunology. agnathan and chondrichthian divergence, the genetic raw materials for these inven- something mysterious, even miraculous oc- tions, but no conclusive evidence of MHC, Rearranging Antigen Receptors. Much atten- curred: the adaptive immune system Ig, TCR, or RAG elements exists in meta- tion has focused on the epicenter of rear- evolved. A complex, interdependent system zoans that diverged before chondrichthyes. rangement, RAG1͞2, the lymphocyte- of checks and balances in which fragments Luminaries in the field of evolution and specific proteins that create nicks between of both intracellular and extracellularly de- immunity describe the critical events that germline chromosomal V, D, and J compo- rived foreign molecules (antigens) are pre- befell our last common ancestor with nents of Igs and TCR. The curious genomic sented in the clutch of MHC cell surface sharks between 500 and 450 million years proximity of RAG1 and -2, their absence of molecules to 1016 possible different lympho- ago in cosmic terms. Synthesizing many introns (5), and their detection in sharks but cyte receptors arose seemingly overnight in recent findings, Schluter et al. (3) describe not protochordates first inspired the hypoth- evolutionary time. Moreover, the system the origin of the combinatorial immune esis of their origin by horizontal transfer to that evolved before the divergence of jawed system with the moniker ‘‘Immunological a vertebrate ancestor (6). Similarity between fish was so successful that the basic para- Big Bang.’’ As in astrophysics, the study of the mechanisms of DNA cleavage for RAG digm remained throughout the radiation of immunology must infer the events of the recombination, retroviral integration, and subsequent vertebrate lineages. past from the stuff—whether electromag- transposition corroborated the hypothesis The immune mechanisms shared by all netic or genetic—that remains today. This that RAG1 and RAG2 entered together on vertebrates are collectively termed ‘‘adap- endeavor is complicated by the possibility a retrotransposon (7–11). It is thought that tive immunity,’’ ‘‘combinatorial immunity,’’ that genetic mechanisms and selective a retrotransposon containing RAG1 and -2 or the ‘‘anticipatory response’’ (1) for the forces exerted by parasites differed in the integrated into a large cis promoter ele- unique receptors generated in response to era of early vertebrates—as did the physics ment. Once translated, RAG proteins me- foreign invaders, or antigens, such as mi- of the nascent universe. Although molec- diated transposition of a gene segment crobes, parasites, and genetically altered ular evolutionists rely on the genomes of flanked by short recombination signal se- cells. Unlike the innate immune compo- extant organisms to peer back in time, this quences (RSS) into a primordial receptor nents found in all multicellular organisms, is commonly misunderstood to be like gene, first splitting the gene into fragments this response is specific, selective, remem- gazing at the light from stars millions of that became V, D, and J through duplication bered, and regulated. T and B lymphocytes, light years away. The genome of living (12). Whether RAG fortuitously planted which bear unique immunoreceptors, circu- sharks is neither ancestral to nor older itself into a uniquely lymphoid promoter or late throughout the body in search of anti- than that of humans, but their comparison acquired specificity later is unclear. gens. B cell receptors, called immunoglobu- may reveal structures that existed in their Non-Rearranging Ig-Like Receptors. lins (Ig), recognize intact macromolecular last common ancestor 450 million years Ig and TCR molecules feature a structural motif complexes on the invaders; the cell progeny ago. comprised of ␤-pleated sheets, known as the of B cells secrete massive amounts of the With the unavailability of either fossilized ‘‘Ig fold,’’ whose archtypical presence in specific Igs, known as antibodies, that per- Cambrian nucleic acid or time travel, evo- receptors and adhesion molecules through meate the intercellular milieu. By contrast, lutionary immunologists primarily rely on phylum Chordata and even in invertebrates T cell receptors (TCRs) recognize small comparative tools using extant species. Re- (13, 14) dates it before the entrance of fragments of antigen presented in the cent investigations into the phylogenetic or- RAG. Many investigations have ap- groove of the MHC (major histocompati- igin of this complex system derive from four proached the hypothesized primordial re- bility complex) receptor found on nearly different approaches: (i) the study of the ceptor by searching for relics of Ig-type every cell in the body. TCR and Ig are evolution of rearranging receptors, (ii)the molecules in classes of organisms that di- encoded by interspersed V, D, and J subge- study of the origin and assembly of MHC, verged before agnathans. Sequences iso- neic elements that are combinatorially re- (iii) the study of the origins of self-nonself lated from hagfish (15, 16), tunicate (17), arranged during lymphocyte development; recognition systems such as histocompati- and sponge (14, 18) aligned with canonical rearrangement is initiated by a unique DNA bility, and (iv) the study of lymphocyte phy- Ig domains produce a similarity score that splicing enzyme complex, the recombinase logeny. A paper in this issue of PNAS by falls into the ‘‘twilight zone’’ of questionable activating genes (RAGs). Each lymphocyte Shintani et al. (4) advances our understand- expresses about 105 identical products of ing of the cellular mediators of adaptive one successful V(D)J rearrangement pair, immunity by tracing the origins of the Spi See companion article on page 7417. and collectively the antigen receptors of T family of lymphocyte-specific transcription †To whom reprint requests should be addressed. E-mail: and B lymphocytes anticipate the full rep- factors in the jawless fish. Here we attempt [email protected]. 6924–6926 ͉ PNAS ͉ June 20, 2000 ͉ vol. 97 ͉ no. 13 Downloaded by guest on October 9, 2021 homology (19). Another line of investiga- MHC. It is difficult to imagine a need for lead to identification of these histocompat- tion begins with the analysis of vertebrate peptide-presenting MHC receptors before ibility genes. non-rearranging Ig-like receptors in hopes the existence of TCRs that simultaneously of gleaning information about the structure bind MHC and peptide. To date, MHC Lymphocytes. Another approach to the of the ancestral pre-RAG receptor. One receptors have not been isolated in species problem of immune evolution is to inquire such group of related receptors includes the that lack RAG or TCR. However, each type into the phylogenetic origins of the cellular paired Ig-like receptors (PIR) in mice (20, of MHC receptor resides in its own genetic bearers of recombined receptors. One 21), the Ig-like transcripts (ILT) in humans locus spanning 2,000–3,000 kb and contain- would like to know the characteristics of [also called leukocyte inhibitory receptors ing many linked immune and some non- lymphocytes in that ancestral recipient of (LIR) or monocyte inhibitory receptors immune genes, including complement and the first RAG transposon; whether separate (MIR) (22)], and the killer inhibitory recep- inflammatory genes. Because many of the T and B cell lineages existed before TCR tors (KIR) of humans (23). The PIR, ILT, genes associated with vertebrate MHC loci and Ig; and what mechanisms of lymphocyte are phylogenetically conserved and perform fate determination were in place. The paper and KIR multigene families are located in functions common to all metazoans, it is by Shintani et al. (4) in this issue makes an syntenic regions of the mouse and human feasible to test linkage between homologs of important foray into this question with the genomes. Members of these receptor fami- MHC-related genes in nonvertebrate spe- identification and characterization of the lies vary slightly in their extracellular Ig cies (2). In the earliest known chordates, the ancestor to a family of lymphocyte transcrip- domain, and they come in two functionally protochordates, close linkage is not ob- tion factors called Spi. In mammals, three distinct forms. They either possess intracel- served between two HSP70 genes, which are known family members, Spi-1 (also called lular tyrosine-based inhibitory motifs contained in the MHC region of verte- PU.1), Spi-B, and Spi-C, are present at (ITIM) to serve as inhibitory receptors, or brates, or to the self-nonself histocompati- various points of lymphocyte lineage and they have transmembrane region polarity bility system called Fu͞HC (refs. 25 and 26; interact via an Ets DNA-binding domain to allowing them to associate with another see below). It remains to be tested whether turn on many genes important in lympho- transmembrane chain containing a ty- homologs of other MHC-associated genes cyte development. Jan Klein’s group has rosine-based activation motif (ITAM) to such as TNF, LMP, TAP, complement, and isolated a single homolog of the Spi genes in form a cell activating receptor complex. The collagen lie in genetic proximity in ag- the jawless fish, as verified by both amino ligands so far identified for these pairs of nathans or protochordates. The present acid similarity and exon structure. Data not activating and inhibitory receptors include data suggest that the MHC assembled very presented in the paper confirm that no other MHC class I and class I-like molecules.
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