The astonishing diversity of Ig classes and B cell repertoires in teleost fish

Abstract

With lymphoid tissue anatomy different than mammals, and diverse adaptations to all aquatic environments, fish constitute a fascinating group of vertebrate to study the biology of B cell repertoires in a comparative perspective. Fish B lymphocytes express immunoglobulin (Ig) on their surface and secrete antigen-specific antibodies in response to immune challenges. Three antibody classes have been identified in fish, namely IgM, IgD, and IgT, while IgG, IgA, and IgE are absent. IgM and IgD have been found in all fish species analyzed, and thus seem to be primordial antibody classes. IgM and IgD are normally co-expressed from the same mRNA through alternative splicing, as in mammals. Tetrameric IgM is the main antibody class found in serum. Some species of fish also have IgT, which seems to exist only in fish and is specialized in mucosal immunity. IgM/IgD and IgT are expressed by two different sub-populations of B cells. The tools available to investigate B cell responses at the cellular level in fish are limited, but the progress of fish genomics has started to unravel a rich diversity of IgH and immunoglobulin light chain locus organization, which might be related to the succession of genome remodelings that occurred during fish evolution. Moreover, the development of deep sequencing techniques has allowed the investigation of the global features of the expressed fish B cell repertoires in zebrafish and rainbow trout, in steady state or after infection. This review provides a description of the organization of fish Ig loci, with a particular emphasis on their heterogeneity between species, and presents recent data on the structure of the expressed Ig repertoire in healthy and infected fish.

Keywords: B cells; antibody; evolution; fish; repertoire.

Figure 1

Milestones of genome evolution within the fish lineage. A few key events of tetraploidization/re-diploidization and contraction are represented. Note that red arrows indicate a segment on the tree where an event is assumed, not a precise time point. The time arrow is not on scale.

Figure 2

Schematic structure of IgH loci in different teleost species. (A) IgH loci with archetypic structure in zebrafish, grass carp, and fugu. (B) Variants of IgH structure found in other species with partial or complete duplications present in different chromosomes (Chr.) (Atlantic salmon, rainbow trout) or in the same chromosome (channel catfish, three-spined stickleback, and Japanese medaka) (Chr.). The schemes are not in scale and depict the genomic configuration of V sets (black boxes), D and J sets (narrow gray boxes), and CH gene sets. Cμ are represented as green boxes, Cδ as red boxes, and Cτ/ζ as blue boxes. The number of in frame V genes and CH exons are indicated in brackets within boxes. CH sequences with frameshift mutations are considered as pseudogenes (Ψ). Catfish IgH: Cδ_s and Cδ_m correspond to the secreted and membrane IgD coding genes, respectively. Medaka IgH: in the Cδ^a, the genomic sequence presents a gap and the actual number of Cδ domains is unknown; Cδ^b indicates the presence of Cμ domains inserted between Cδ exons. The “?” symbol indicates a lack of data. (C) Detailed exon structure of the IgHA μ−δ region in Atlantic salmon.

Figure 3

Representation of IgH splicing alternative pathways in fish and tetrapods. The alternative splicing leading to IgHμ (plain line) and to IgHδ (dotted line) mature mRNAs (A). IgHμ RNA splicing pathways in different fish groups and in Tetrapods (B): plain and dotted lines represent general and alternative splicing pathways, respectively.

Figure 4

Typical normalized distributions of JST in the pyrosequencing datasets. JST observed n times from control and virus infected fish for a given VH/C combination are represented as percentages of the total number of JST. Large clonal expansions are indicated by high number of occurrences of expressed JST in infected animals.