Vertebrate Adaptive Immune System Research Articles

Discovery of an unconventional lamprey lymphocyte lineage highlights divergent features in vertebrate adaptive immune system evolution

Lymphocyte receptors independently evolved in both jawed and jawless vertebrates with similar adaptive immune responses. However, the diversity of functional subtypes and molecular architecture in jawless vertebrate lymphocytes, comparable to jawed species, is not well defined. Here, we profile the gills, intestines, and blood of the lamprey, Lampetra morii, with single-cell RNA sequencing, using a full-length transcriptome as a reference. Our findings reveal higher tissue-specific heterogeneity among T-like cells in contrast to B-like cells. Notably, we identify a unique T-like cell subtype expressing a homolog of the nonlymphoid hematopoietic growth factor receptor, MPL-like (MPL-L). These MPL-L+ T-like cells exhibit features distinct from T cells of jawed vertebrates, particularly in their elevated expression of hematopoietic genes. We further discovered that MPL-L+ VLRA+ T-like cells are widely present in the typhlosole, gill, liver, kidney, and skin of lamprey and they proliferate in response to both a T cell mitogen and recombinant human thrombopoietin. These findings provide new insights into the adaptive immune response in jawless vertebrates, shedding new light on the evolution of adaptive immunity.

Mechanisms underlying the direct programming of mouse embryonic fibroblasts to thymic epithelial cells by FOXN1.

Thymic epithelial cells (TECs) are crucial to the ability of the thymus to generate T cells for the adaptive immune system in vertebrates. However, no in vitro system for studying TEC function exists. Overexpressing the transcription factor FOXN1 initiates transdifferentiation of fibroblasts into TEC-like cells (iTECs) that support T-cell differentiation in culture or after transplant. In this study, we have characterized iTEC programming at the cellular and molecular level in mouse to determine how it proceeds, and have identified mechanisms that can be targeted for improving this process. These data show that iTEC programming consists of discrete gene expression changes that differ early and late in the process, and that iTECs upregulate markers of both cortical and medullary TEC (cTEC and mTEC) lineages. We demonstrate that promoting proliferation enhances iTEC generation, and that Notch inhibition allows the induction of mTEC differentiation. Finally, we show that MHCII expression is the major difference between iTECs and fetal TECs. MHCII expression was improved by co-culturing iTECs with fetal double-positive T-cells. This study supports future efforts to improve iTEC generation for both research and translational uses.

Evolutionary variation in gene conversion at the avian MHC is explained by fluctuating selection, gene copy numbers and life history.

The major histocompatibility complex (MHC) multigene family encodes key pathogen-recognition molecules of the vertebrate adaptive immune system. Hyper-polymorphism of MHC genes is de novo generated by point mutations, but new haplotypes may also arise by re-shuffling of existing variation through intra- and inter-locus gene conversion. Although the occurrence of gene conversion at the MHC has been known for decades, we still have limited understanding of its functional importance. Here, I took advantage of extensive genetic resources (~9000 sequences) to investigate broad scale macroevolutionary patterns in gene conversion processes at the MHC across nearly 200 avian species. Gene conversion was found to constitute a universal mechanism in birds, as 83% of species showed footprints of gene conversion at either MHC class and 25% of all allelic variants were attributed to gene conversion. Gene conversion processes were stronger at MHC-II than MHC-I, but inter-specific variation at both MHC classes was explained by similar evolutionary scenarios, reflecting fluctuating selection towards different optima and drift. Gene conversion showed uneven phylogenetic distribution across birds and was driven by gene copy number variation, supporting significant role of inter-locus gene conversion processes in the evolution of the avian MHC. Finally, MHC gene conversion was stronger in species with fast life histories (high fecundity) and in long-distance migrants, likely reflecting variation in population sizes and host-pathogen coevolutionary dynamics. The results provide a robust comparative framework for understanding macroevolutionary variation in gene conversion at the avian MHC and reinforce important contribution of this mechanism to functional MHC diversity.

Diversity of major histocompatibility complex of II B gene and mate choice in a monogamous and long-lived seabird, the Little Auk (Alle alle).

The major histocompatibility complex (MHC) plays a key role in the adaptive immune system of vertebrates, and is known to influence mate choice in many species. In birds, the MHC has been extensively examined but mainly in galliforms and passerines while other taxa that represent specific ecological and evolutionary life-histories, like seabirds, are underexamined. Here, we characterized diversity of MHC Class II B exon 2 in a colonial pelagic seabird, the Little Auk (or Dovekie Alle alle). We further examined whether MHC variation could be maintained through balancing selection and disassortative mating. We found high polymorphism at the genotyped MHC fragment, characterizing 99 distinct alleles across 140 individuals from three populations. The alleles frequencies exhibited a similar skewed distribution in both sexes, with the four most commonly occurring alleles representing approximately 35% of allelic variation. The results of a Bayesian site-by-site selection analysis suggest evidence of balancing selection and no direct evidence for MHC-dependent disassortative mating preferences in the Little Auk. The latter result might be attributed to the high overall polymorphism of the examined fragment, which itself may be maintained by the large population size of the species.

Innate and germline immune memory: specificity and heritability of the ancient immune mechanisms for adaptation and survival.

The immune memory is one of the defensive strategies developed by both unicellular and multicellular organisms for ensuring their integrity and functionality. While the immune memory of the vertebrate adaptive immune system (based on somatic recombination) is antigen-specific, encompassing the generation of memory T and B cells that only recognize/react to a specific antigen epitope, the capacity of vertebrate innate cells to remember past events is a mostly non-specific mechanism of adaptation. This "innate memory" can be considered as germline-encoded because its effector tools (such as innate receptors) do not need somatic recombination for being active. Also, in several organisms the memory-related information is integrated in the genome of germline cells and can be transmitted to the progeny for several generations, but it can also be erased depending on the environmental conditions. Overall, depending on the organism, its environment and its living habits, innate immune memory appears to be a mechanism for achieving better protection and survival against repeated exposure to microbes/stressful agents present in the same environment or occurring in the same anatomical district, able to adapt to changes in the environmental cues. The anatomical and functional complexity of the organism and its lifespan drive the generation of different immune memory mechanisms, for optimal adaptation to changes in the living/environmental conditions. The concept of innate immunity being non-specific needs to be revisited, as a wealth of evidence suggests a significant degree of specificity both in the primary immune reaction and in the ensuing memory-like responses. This is clearly evident in invertebrate metazoans, in which distinct scenarios can be observed, with both non-specific (immune enhancement) or specific (immune priming) memory-like responses. In the case of mammals, there is evidence that some degree of specificity can be attained in different situations, for instance as organ-specific protection rather than microorganism-specific reaction. Thus, depending on the challenges and conditions, innate memory can be non-specific or specific, can be integrated in the germline and transmitted to the progeny or be short-lived, thereby representing an exceptionally plastic mechanism of defensive adaptation for ensuring individual and species survival.

John Joseph Thomas Hayes Owen. 7 January 1934—5 January 2023

John Owen was an anatomist and immunologist who conducted pioneering work on the origins and development of the two major classes of lymphocytes, the cells that are the central players in the adaptive immune systems of vertebrates. He was a meticulous biological experimenter who liked to keep questions simple and precise. His observations contributed to two key discoveries: that mouse and avian stem cells migrate into the embryonic thymus and give rise to T lymphocytes; and that in birds the bursa of Fabricius is the tissue in which stem cells develop into B lymphocytes. He also helped to establish that in mammals the earliest B lymphocytes develop in the liver of the fetus. He and his colleagues went on to define how combinations of several cell populations in the thymus provide the settings in which mammals first generate and then select from the variety of T lymphocyte lineages and immune specificities that will equip them with healthy immune surveillance and responses. His wry Liverpudlian sense of humour let him engage easily with everyone, from any walk of life, and he was an inspiration to young colleagues, many of whom would go on to flourish in the research areas that he pioneered. John died on 5 January 2023, from prostate cancer and other ailments: but he was in the gym only a couple of weeks before he died. He is buried in Kirkdale cemetery, Lancashire, under a family tombstone that also celebrates his grandfather, his father and his mother: his epitaph reads ‘One push-up too many’.

Classification and Immune Function of Coelomocytes in Echinoderms

Abstract: The top taxonomic position among non-chordate invertebrates, which make up the evolutionary connection between invertebrates and vertebrates, is held by echinoderms. Their immune responses rely on coelomocyte activity functioning concurrently with a range of humoral components that directly interact with invasive pathogens. However, markedly lower numbers of systematic reviews of the classification and immune function of coelomocytes have been performed compared with those of vertebrates. Studying echinoderm coelomocytes continues to be an important evolutionary vantage point for determining the origins of bilaterian immunity as well as the principles behind the adaptive immune system of vertebrates. This article reviews the classifications and immune functions of coelomocytes (sea urchin, sea cucumber and sea star). It summarizes the research progress on immune-related genes/proteins, signal transduction pathways and effector molecules in echinoderms according to the recent literature. This summary provides a theoretical basis for studying coelomocytes and disease control in echinoderms. In the future, a variety of methods and techniques should be used and combined with the surface receptors of cells to study the classification and function of coelomocytes of echinoderms.

Limited associations between MHC diversity and reproductive success in a bird species with biparental care.

The selective pressure from pathogens on individuals can have direct consequences on reproduction. Genes from the major histocompatibility complex (MHC) are central to the vertebrate adaptive immune system and pathogen resistance. In species with biparental care, each sex has distinct reproductive roles and levels of investment, and due to a trade-off with immunity, one can expect different selective regimes acting upon the MHC of each parent. Here, we addressed whether couples combine each other's variation at MHC loci to increase their breeding success. Specifically, we used a 23-year dataset from a barn owl population (Tyto alba) to understand how MHC class Iα and IIβ functional divergence and supertypes of each parent were associated with clutch size and fledging success. We did not detect associations between MHC diversity and supertypes with the clutch size or with the fledging success. In addition, to understand the relative contribution from the MHC of the genetic parents and the social parents, we analyzed the fledging success using only a cross-fostered dataset. We found several associations of weak-to-moderate effect sizes between the father's MHC and fledging success: (i) lower MHC-Iα divergence in the genetic father increases fledging success, which might improve paternal care during incubation, and (ii) one and two MHC-IIβ DAB2 supertypes in the social father decrease and increase, respectively, fledging success, which may affect the paternal care after hatching. Furthermore, fledging success increased when both parents did not carry MHC-IIβ DAB1 supertype 2, which could suggest conditional effects of this supertype. Although our study relied on a substantial dataset, we showed that the associations between MHC diversity and reproductive success remain scarce and of complex interpretation in the barn owl. Moreover, our results highlighted the need to incorporate more than one proxy of reproductive success and several MHC classes to capture more complex associations.

Comparative genomics of the T cell receptor μ locus in marsupials and monotremes.

T cells are a primary component of the vertebrate adaptive immune system. There are three mammalian T cell lineages based on their T cell receptors (TCR). The αβ T cells and γδ T cells are ancient and found broadly in vertebrates. The more recently discovered γμ T cells are uniquely mammalian and only found in marsupials and monotremes. In this study, we compare the TCRμ locus (TRM) across the genomes of two marsupials, the gray short-tailed opossum and Tasmanian devil, and one monotreme, the platypus. These analyses revealed lineage-specific duplications, common to all non-eutherian mammals described. There is conserved synteny in the TRM loci of both marsupials but not in the monotreme. Our results are consistent with an ancestral cluster organization which was present in the last common mammalian ancestor which underwent lineage-specific duplications and divergence among the non-eutherian mammals.

Origin and evolutionary malleability of T cell receptor α diversity

Lymphocytes of vertebrate adaptive immune systems acquired the capability to assemble, from split genes in the germline, billions of functional antigen receptors1–3. These receptors show specificity; unlike the broadly tuned receptors of the innate system, antibodies (Ig) expressed by B cells, for instance, can accurately distinguish between the two enantiomers of organic acids4, whereas T cell receptors (TCRs) reliably recognize single amino acid replacements in their peptide antigens5. In developing lymphocytes, antigen receptor genes are assembled from a comparatively small set of germline-encoded genetic elements in a process referred to as V(D)J recombination6,7. Potential self-reactivity of some antigen receptors arising from the quasi-random somatic diversification is suppressed by several robust control mechanisms8–12. For decades, scientists have puzzled over the evolutionary origin of somatically diversifying antigen receptors13–16. It has remained unclear how, at the inception of this mechanism, immunologically beneficial expanded receptor diversity was traded against the emerging risk of destructive self-recognition. Here we explore the hypothesis that in early vertebrates, sequence microhomologies marking the ends of recombining elements became the crucial targets of selection determining the outcome of non-homologous end joining-based repair of DNA double-strand breaks generated during RAG-mediated recombination. We find that, across the main clades of jawed vertebrates, TCRα repertoire diversity is best explained by species-specific extents of such sequence microhomologies. Thus, selection of germline sequence composition of rearranging elements emerges as a major factor determining the degree of diversity of somatically generated antigen receptors.

Characteristics and expression profiles of MHC class Ⅰ molecules in Carassius auratus.

Major histocompatibility complex class Ⅰ (MHC Ⅰ) molecules play a vital role in adaptive immune systems in vertebrates by presenting antigens to effector T cells. Understanding the expression profiling of MHC Ⅰ molecules in fish is essential for improving our knowledge of the relationship between microbial infection and adaptive immunity. In this study, we conducted a comprehensive analysis of MHC Ⅰ gene characteristics in Carassius auratus, an important freshwater aquaculture fish in China that is susceptible to Cyprinid herpesvirus 2 (CyHV-2) infection. We identified approximately 20 MHC Ⅰ genes discussed, including U, Z, and L lineage genes. However, only U and Z lineage proteins were identified in the kidney of Carassius auratus using high pH reversed-phase chromatography and mass spectrometry. The L lineage proteins were either not expressed or present at an extremely low level in the kidneys of Carassius auratus. We also used targeted proteomics to analyze changes in protein MHC Ⅰ molecules abundance in healthy and CyHV-2-infected Carassius auratus. We observed that five MHC Ⅰ molecules were upregulated, and Caau-UFA was downregulated in the diseased group. This study is the first to reveal the expression of MHC Ⅰ molecules at a large scale in Cyprinids, which enhances our understanding of fish adaptive immune systems.

Evidence for Extensive Duplication and Subfunctionalization of FCRL6 in Armadillo (Dasypus novemcinctus).

The control of infections by the vertebrate adaptive immune system requires careful modulation to optimize defense and minimize harm to the host. The Fc receptor-like (FCRL) genes encode immunoregulatory molecules homologous to the receptors for the Fc portion of immunoglobulin (FCR). To date, nine different genes (FCRL1-6, FCRLA, FCRLB and FCRLS) have been identified in mammalian organisms. FCRL6 is located at a separate chromosomal position from the FCRL1-5 locus, has conserved synteny in mammals and is situated between the SLAMF8 and DUSP23 genes. Here, we show that this three gene block underwent repeated duplication in Dasypus novemcinctus (nine-banded armadillo) resulting in six FCRL6 copies, of which five appear functional. Among 21 mammalian genomes analyzed, this expansion was unique to D. novemcinctus. Ig-like domains that derive from the five clustered FCRL6 functional gene copies show high structural conservation and sequence identity. However, the presence of multiple non-synonymous amino acid changes that would diversify individual receptor function has led to the hypothesis that FCRL6 endured subfunctionalization during evolution in D. novemcinctus. Interestingly, D. novemcinctus is noteworthy for its natural resistance to the Mycobacterium leprae pathogen that causes leprosy. Because FCRL6 is chiefly expressed by cytotoxic T and NK cells, which are important in cellular defense responses against M. leprae, we speculate that FCRL6 subfunctionalization could be relevant for the adaptation of D. novemcinctus to leprosy. These findings highlight the species-specific diversification of FCRL family members and the genetic complexity underlying evolving multigene families critical for modulating adaptive immune protection.

Review of the unique and dominant lectin pathway of complement activation in agnathans

As the most primitive vertebrates, lampreys are significant in understanding the early origin and evolution of the vertebrate innate and adaptive immune systems. The complement system is a biological response system with complex and precise regulatory mechanisms and plays an important role in innate and adaptive immunity. It consists of more than 30 distinct components, including intrinsic components, regulatory factors, and complement receptors. Complement system is the humoral backbone of the innate immune defense and complement-like factors have also been found in cyclostomes. Our knowledge as such in lamprey has dramatically increased in the recent years. The searching for complement components in the reissner lamprey Lethenteron reissneri genome database, together with published data, has unveiled the existence of all the orthologues of mammalian complement components identified thus far, including the complement regulatory proteins and complement receptors, in lamprey. This review, summarizes the key themes and recent updates on the complement system of agnathans and discusses the individual complement components of lampreys, and critically compare their functions to that of mammalian complement components. Interestingly, the adaptive immune system of agnathans differs from that of gnathostomes. Lamprey complement components also display some distinctive features, such as lampreys are characterized by the variable lymphocyte receptors (VLRs)-based alternative adaptive immunity. This review may serve as important literature for deducing the evolution of the immune system from invertebrates to vertebrates.

Functional antibodies exhibit light chain coherence

The vertebrate adaptive immune system modifies the genome of individual B cells to encode antibodies that bind particular antigens1. In most mammals, antibodies are composed of heavy and light chains that are generated sequentially by recombination of V, D (for heavy chains), J and C gene segments. Each chain contains three complementarity-determining regions (CDR1–CDR3), which contribute to antigen specificity. Certain heavy and light chains are preferred for particular antigens2–22. Here we consider pairs of B cells that share the same heavy chain V gene and CDRH3 amino acid sequence and were isolated from different donors, also known as public clonotypes23,24. We show that for naive antibodies (those not yet adapted to antigens), the probability that they use the same light chain V gene is around 10%, whereas for memory (functional) antibodies, it is around 80%, even if only one cell per clonotype is used. This property of functional antibodies is a phenomenon that we call light chain coherence. We also observe this phenomenon when similar heavy chains recur within a donor. Thus, although naive antibodies seem to recur by chance, the recurrence of functional antibodies reveals surprising constraint and determinism in the processes of V(D)J recombination and immune selection. For most functional antibodies, the heavy chain determines the light chain.

Cytokine Receptor Diversity in the Lamprey Predicts the Minimal Essential Cytokine Networks of Vertebrates.

The vertebrate adaptive immune systems (Agnatha and Gnathostomata) use sets of T and B lymphocyte lineages that somatically generate highly diverse repertoires of Ag-specific receptors and Abs. In Gnathostomata, cytokine networks regulate the activation of lymphoid and myeloid cells, whereas little is known about these components in Agnathans. Most gnathostome cytokines are four-helix bundle cytokines with poorly conserved primary sequences. In contrast, sequence conservation across bilaterians has been observed for cognate cytokine receptor chains, allowing their structural classification into two classes, and for downstream JAK/STAT signaling mediators. With conserved numbers among Gnathostomata, human cytokine receptor chains (comprising 34 class I and 12 class II) are able to interact with 28 class I helical cytokines (including most ILs) and 16 class II cytokines (including all IFNs), respectively. Hypothesizing that the arsenal of cytokine receptors and transducers may reflect homologous cytokine networks, we analyzed the lamprey genome and transcriptome to identify genes and transcripts for 23 class I and five class II cytokine receptors alongside one JAK signal mediator and four STAT transcription factors. On the basis of deduction of their respective orthologs, we predict that these receptors may interact with 16 class I and 3 class II helical cytokines (including IL-4, IL-6, IL-7, IL-12, IL-10, IFN-γ, and thymic stromal lymphoprotein homologs). On the basis of their respective activities in mammals, this analysis suggests the existence of lamprey cytokine networks that may regulate myeloid and lymphoid cell differentiation, including potential Th1/Th2 polarization. The predicted networks thus appear remarkably homologous to those of Gnathostomata, albeit reduced to essential functions.

MHCtools - an R package for MHC high-throughput sequencing data: Genotyping, haplotype and supertype inference, and downstream genetic analyses in non-model organisms.

The major histocompatibility complex (MHC) plays a central role in the vertebrate adaptive immune system and has been of long‐term interest in evolutionary biology. While several protocols have been developed for MHC genotyping, there is a lack of transparent and standardized tools for downstream analysis of MHC data. Here, we present the r package mhctools and demonstrate the use of its functions to (i) assist accurate MHC genotyping from high‐throughput amplicon‐sequencing data, (ii) infer functional MHC supertypes using bootstrapped clustering analysis, (iii) identify segregating MHC haplotypes from family data, and (iv) analyse functional and genetic distances between MHC sequences. We employed mhctools to analyse MHC class I (MHC‐I) amplicon data of 559 great reed warblers (Acrocephalus arundinaceus). We identified 390 MHC‐I alleles which clustered into 14 functional supertypes. A phylogenetic analysis and analyses of positive selection suggested that the MHC‐I alleles belong to several distinct functional groups. We furthermore identified 107 segregating haplotypes among 116 families, and found substantial variation in diversity with 4–21 MHC‐I alleles and 3–13 MHC‐I supertypes per haplotype. Finally, we show that the great reed warbler haplotypes harboured combinations of MHC‐I supertypes with greater functional divergence than observed in simulated populations of possible haplotypes, a result that is in accordance with the divergent allele advantage hypothesis. Our study demonstrates the power of mhctools to support genotyping and analysis of MHC in non‐model species, which we hope will encourage broad implementation among researchers in MHC genetics and evolution.

A scaling law in CRISPR repertoire sizes arises from the avoidance of autoimmunity

Some prokaryotes possess CRISPR-Cas systems that use DNA segments called spacers, which are acquired from invading phages, to guide immune defense. Here, we propose that cross-reactive CRISPR targeting can, however, lead to "heterologous autoimmunity," whereby foreign spacers guide self-targeting in a spacer-length-dependent fashion. Balancing antiviral defense against autoimmunity predicts a scaling relation between spacer length and CRISPR repertoire size. We find evidence for this scaling through a comparative analysis of sequenced prokaryotic genomes and show that this association also holds at the level of CRISPR types. By contrast, the scaling is absent in strains with nonfunctional CRISPR loci. Finally, we demonstrate that stochastic spacer loss can explain variations around the scaling relation, even between strains of the same species. Our results suggest that heterologous autoimmunity is a selective factor shaping the evolution of CRISPR-Cas systems, analogous to the trade-offs between immune specificity, breadth, and autoimmunity that constrain the diversity of adaptive immune systems in vertebrates.

Comparative assessment of immunological tolerance in fish with natural immunodeficiency

Natural occurrences of immunodeficiency by definition should lead to compromised immune function. The major histocompatibility complexes (MHC) are key components of the vertebrate adaptive immune system, charged with mediating allorecognition and antigen presentation functions. To this end, the genomic loss of the MHC II pathway in Syngnathus pipefishes raises questions regarding their immunological vigilance and allorecognition capabilities. Utilising allograft and autograft fin-transplants, we compared the allorecognition immune responses of two pipefish species, with (Nerophis ophidion) and without (Syngnathus typhle) a functional MHC II. Transcriptome-wide assessments explored the immunological tolerance and potential compensatory measures occupying the role of the absent MHC II. Visual observations suggested a more acute rejection response in N. ophidion allografts compared with S. typhle allografts. Differentially expressed genes involved in innate immunity, angiogenesis and tissue recovery were identified among transplantees. The intriguing upregulation of the cytotoxic T-cell implicated gzma in S. typhle allografts, suggests a prominent MHC I related response, which may compensate for the MHC II and CD4 loss. MHC I related downregulation in N. ophidion autografts hints at an immunological tolerance related reaction. These findings may indicate alternative measures evolved to cope with the MHC II genomic loss enabling the maintenance of appropriate tolerance levels. This study provides intriguing insights into the immune and tissue recovery mechanisms associated with syngnathid transplantation, and can be a useful reference for future studies focusing on transplantation transcriptomics in non-model systems.

Reconstructing Macroevolutionary Patterns in Avian MHC Architecture With Genomic Data.

The Major Histocompatibility Complex (MHC) is a hyper-polymorphic genomic region, which forms a part of the vertebrate adaptive immune system and is crucial for intra- and extra-cellular pathogen recognition (MHC-I and MHC-IIA/B, respectively). Although recent advancements in high-throughput sequencing methods sparked research on the MHC in non-model species, the evolutionary history of MHC gene structure is still poorly understood in birds. Here, to explore macroevolutionary patterns in the avian MHC architecture, we retrieved contigs with antigen-presenting MHC and MHC-related genes from available genomes based on third-generation sequencing. We identified: 1) an ancestral avian MHC architecture with compact size and tight linkage between MHC-I, MHC-IIA/IIB and MHC-related genes; 2) three major patterns of MHC-IIA/IIB unit organization in different avian lineages; and 3) lineage-specific gene translocation events (e.g., separation of the antigen-processing TAP genes from the MHC-I region in passerines), and 4) the presence of a single MHC-IIA gene copy in most taxa, showing evidence of strong purifying selection (low dN/dS ratio and low number of positively selected sites). Our study reveals long-term macroevolutionary patterns in the avian MHC architecture and provides the first evidence of important transitions in the genomic arrangement of the MHC region over the last 100 million years of bird evolution.

On the relationship between extant innate immune receptors and the evolutionary origins of jawed vertebrate adaptive immunity.

For over half a century, deciphering the origins of the genomic loci that form the jawed vertebrate adaptive immune response has been a major topic in comparative immunogenetics. Vertebrate adaptive immunity relies on an extensive and highly diverse repertoire of tandem arrays of variable (V), diversity (D), and joining (J) gene segments that recombine to produce different immunoglobulin (Ig) and T cell receptor (TCR) genes. The current consensus is that a recombination-activating gene (RAG)-like transposon invaded an exon of an ancient innate immune VJ-bearing receptor, giving rise to the extant diversity of Ig and TCR loci across jawed vertebrates. However, a model for the evolutionary relationships between extant non-recombining innate immune receptors and the V(D)J receptors of the jawed vertebrate adaptive immune system has only recently begun to come into focus. In this review, we provide an overview of non-recombining VJ genes, including CD8β, CD79b, natural cytotoxicity receptor 3 (NCR3/NKp30), putative remnants of an antigen receptor precursor (PRARPs), and the multigene family of signal-regulatory proteins (SIRPs), that play a wide range of roles in immune function. We then focus in detail on the VJ-containing novel immune-type receptors (NITRs) from ray-finned fishes, as recent work has indicated that these genes are at least 50 million years older than originally thought. We conclude by providing a conceptual model of the evolutionary origins and phylogenetic distribution of known VJ-containing innate immune receptors, highlighting opportunities for future comparative research that are empowered by this emerging evolutionary perspective.