Lymphoid Tissue in Teleost Gills: Variations on a Theme.

In bony fish, the gill filaments are essential for gas exchanges, but also are vulnerable to infection by water-borne microorganisms. Omnipresent across fish, gill-associated lymphoid tissues (GIALT) regulate interactions with local microbiota and halt infection by pathogens. A special GIALT structure has recently been found in Salmonids, the interbranchial lymphoid tissue (ILT). However, the structural variation of GIALT across bony fish remains largely unknown. Here, we show how this critical zone of interaction evolved across fishes. By labeling a conserved T-cell epitope on tissue sections, we find that several basal groups of teleosts possess typical ILT, while modern teleosts have lymphoepithelium of different shape and size at the base of primary gill filaments. Within Cypriniformes, neither body size variation between two related species, zebrafish and common carp, nor morphotype variation, did have a drastic effect on the structure of ILT. Thereby this study is the first to describe the presence of ILT in zebrafish. The ILT variability across fish orders seems to represent different evolutionary solutions to balancing trade-offs between multiple adaptations of jaws and pharyngeal region, and immune responses. Our data point to a wide structural variation in gill immunity between basal groups and modern teleosts.

New perspectives for large-scale repertoire analysis of immune receptors.

In vertebrates, the world of antigenic motifs is matched to large populations of lymphocytes through specific recognition of an epitope by a given receptor unique to a lymphocyte clone. The concept of immune repertoire was proposed to describe this diversity of lymphocyte receptors - Ig and TCR - required by the network of interactions. The immune repertoires became useful tools to describe lymphocyte and receptor populations through the development of the immune system and in pathological situations. Recently, the development of mass technologies made possible a comprehensive survey of immune repertoires at the genome, transcript and protein levels, and some of these techniques have been already adapted to TCR and Ig repertoire analyses. Such approaches generate very big datasets, which necessitates complex and multi-parametric annotations in dedicated databases. They also require new analysis methods, leading to the integration of structure and dynamics of the immune repertoires, at different time scales (immune response, development of the individual, evolution of the species). Such methods may be extended to the analysis of new classes of adaptive-like receptors, which were recently discovered in different invertebrates and in agnathans. Ultimately, they may allow a parallel monitoring of pathogen and immune repertoires addressing the reciprocal influences that decide for the host survival or death. In this review, we first study the characteristics of Ig and TCR repertoires, and we examine several systematic approaches developed for the analysis of these "classical" immune repertoires at different levels. We then consider examples of the recent developments of modeling and statistical analysis, and we discuss their relevance and their importance for the study of the immune diversity. An extended view of immune repertoires is proposed, integrating the diversity of other receptors involved in immune recognition. Also, we discuss how repertoire studies could link pathogen variation and immune diversity to reveal regulatory patterns and rules driving their co-diversification race.

Germline and somatic diversification of immune recognition elements in Metazoa.

The histories of the immune systems of Metazoa during evolution are envisaged like as many adaptations to the continuous diversification of immune receptors and effectors genes under the pressure of changing environments. A basic diversity of potential immune receptor genes existed in primitive Metazoa. Their subsequent recruitment into immunity, their diversification revolving around the conservation of signaling cascades was paralleled by cell specialization and the introduction of regulatory networks. Polymorphism, duplication and somatic mechanisms of diversification affected independently and still affect different gene families in many phyla, creating a greater variety of immune system exhibiting sometimes little homology but much analogy to one another. Diversity and multiplicity of receptors was generated by duplication and creation of multigene families. Independently in several phyla further diversity is created somatically by alternate splicing, somatic mutation, gene conversion and gene rearrangement. In several instances combinatorial usage of polypeptide chains or genes segments increases the repertoire of the recognition structures. Metazoa had to adapt to the conditions generated by this diversity: the control of expression of multiple genes and the risk of autoimmunity.

Evidence for a functional second thymus in mice.

The thymus organ supports the development of T cells and is located in the thorax. Here, we report the existence of a second thymus in the mouse neck, which develops after birth and grows to the size of a small lymph node. The cervical thymus had a typical medulla-cortex structure, was found to support T cell development, and could correct T cell deficiency in athymic nude mice upon transplantation. The identification of a regular second thymus in the mouse may provide evolutionary links to thymus organogenesis in other vertebrates and suggests a need to reconsider the effect of thoracic thymectomy on de novo T cell production.

On the origins of the adaptive immune system: novel insights from invertebrates and cold-blooded vertebrates.

When and how adaptive immunity emerged is one of the fundamental questions in immunology. Accumulated evidence suggests that the key components of adaptive immunity, rearranging receptor genes and the MHC, are unique to jawed vertebrates. Recent studies in protochordates, in particular, the draft genome sequence of the ascidian Ciona intestinalis, are providing important clues for understanding the origin of antigen receptors and the MHC. We discuss a group of newly identified protochordate genes along with some cold-blooded vertebrate genes, the ancestors of which might have provided key elements of antigen receptors. The organization of the proto-MHCs in protochordates provides convincing evidence that the MHC regions of jawed vertebrates emerged as a result of two rounds of chromosomal duplication.

The fate of duplicated major histocompatibility complex class Ia genes in a dodecaploid amphibian, Xenopus ruwenzoriensis.

The dodecaploid anuran amphibian Xenopus ruwenzoriensis represents the only polyploid species of Xenopus in which the full silencing of the extra copies of the major histocompatibility complex (MHC) has not occurred. Xenopus ruwenzoriensis is a recent polyploid that has evolved within one of the two tetraploid groups of Xenopus through allopolyploidization. Family studies of its MHC haplotype suggested a polysomic inheritance of the MHC class I and II genes. Four class Ia bands can be detected per individual in Southern blot analysis and, similarly, four different cDNA sequences are expressed per individual. The Xenopus class Ia sequences we analyzed belong to only one of the old class I lineages and show a homogenization of their alpha3 domain sequences. This homogenization occurred after speciation within the Xenopus ruwenzoriensis species, either due to gene conversion or inter-alleles/loci recombination.A re-evaluation of the polymorphism of class Ia in Xenopus, by looking at the rate of non-synonymous versus synonymous substitutions, suggests that Xenopus MHC class Ia genes are not under strong overdominant selection. This is a rare situation among vertebrates. The observed polymorphism is most likely due to the interlocus genetic exchanges related to the peculiar mode of speciation of the genus.

The fate of duplicated major histocompatibility complex class Ia genes in a dodecaploid amphibian, Xenopus ruwenzoriensis.

The dodecaploid anuran amphibian Xenopus ruwenzoriensis represents the only polyploid species of Xenopus in which the full silencing of the extra copies of the major histocompatibility complex (MHC) has not occurred. Xenopus ruwenzoriensis is a recent polyploid that has evolved within one of the two tetraploid groups of Xenopus through allopolyploidization. Family studies of its MHC haplotype suggested a polysomic inheritance of the MHC class I and II genes. Four class Ia bands can be detected per individual in Southern blot analysis and, similarly, four different cDNA sequences are expressed per individual. The Xenopus class Ia sequences we analyzed belong to only one of the old class I lineages and show a homogenization of their alpha3 domain sequences. This homogenization occurred after speciation within the Xenopus ruwenzoriensis species, either due to gene conversion or inter-alleles/loci recombination.A re-evaluation of the polymorphism of class Ia in Xenopus, by looking at the rate of non-synonymous versus synonymous substitutions, suggests that Xenopus MHC class Ia genes are not under strong overdominant selection. This is a rare situation among vertebrates. The observed polymorphism is most likely due to the interlocus genetic exchanges related to the peculiar mode of speciation of the genus.

Two highly divergent ancient allelic lineages of the transporter associated with antigen processing (TAP) gene in Xenopus: further evidence for co-evolution among MHC class I region genes.

In the frog Xenopus, MHC class I antigen presentation and processing genes (the immunoproteasome LMP2 and LMP7 and the transporter TAP1 and TAP2) seem to be closely linked in a primordial organization. Two distinct lineages of class Ia and LMP7 loci were previously identified, thus strongly suggesting co-evolution among 'class I region' genes. We now show that the Xenopus MHC 'class I region' lies between class II and class III genes and we have isolated two distinct alleles at both the TAP1 and TAP2 loci. The alleles at each locus are remarkably divergent from each other and phylogenetic tree analysis revealed in both cases that they diverged from each other 60-100 million years ago (MYA). For lineage-frequency and linkage analysis, 25 wild-caught X. laevis and 16 X. tropicalis were examined. The two lineages were present in different frequencies for X. laevis and X. tropicalis. Nevertheless, in all cases, the LMP7, TAP1, and TAP2 lineages were found in a set comprising one of the two lineages. Furthermore, like the LMP7 lineages, the TAP lineages were detected in most Xenopus species that diverged from a common ancestor 80-100 MYA, suggesting that the 'class I region' biallelic lineages are under balancing selection.