Prototypic T cell receptor and CD4-like coreceptor are expressed by lymphocytes in the agnathan sea lamprey

Abstract

All jawed vertebrates have highly diverse lymphocyte receptors, which allow discrimination between self and nonself antigens as well as the recognition of potential pathogens. Key elements of the anticipatory recombinatorial immune system in jawed vertebrates are the TCR, Ig, and MHC genes, but their ancestral genes have not been found in more basal vertebrates. In this study, we extended our analysis of the transcriptome of lymphocyte-like cells in the lamprey to identify the TCR-like and CD4-like genes. The structural features of these genes and their preferential expression in lymphocytes make them attractive candidates for ancestral TCR and CD4 genes. The TCR-like gene contains both V (variable) and J (joining) sequences in its first exon and exists as a single-copy gene that is invariant. Thus, the TCR-like gene cannot account for the receptor diversity that is required for the immune responses reported for lamprey, but it could have been easily modified to serve as an evolutionary precursor of modern TCR and Ig genes.S pecific adaptive immunity emerged during vertebrate evolution as a new strategy for coping with an antigenic world of infinite variety. This anticipatory immune system (AIS) in jawed vertebrates is based on diverse lymphocyte receptors, which are assembled by means of combinatorial rearrangement of Ig V (variable), D (diversity), and J (joining) gene segments. The recombination-activating genes, RAG1 and RAG2, catalyze the joining of V(D)J gene segments to generate unique antigenbinding regions of the B cell receptors and T cell receptors (TCRs). The complementary arm of the AIS is provided by the polymorphic MHC genes for class I and II molecules that present antigenic peptides to TCR-bearing lymphocytes. The TCR, Ig, and MHC genes are conserved in all jawed vertebrates that have been studied, including representatives of the oldest extant group of cartilaginous fish: the sharks, skates, and rays (1-3).The evolutionary origin of the TCR, Ig, and MHC genes is still unknown, but precursors of these key AIS elements would be anticipated in ancestors of the jawed vertebrates. The chordate phylum derived from urochordate ancestors, some of which evolved into the cephalochordates. However, these basal chordates lack identifiable orthologs of pivotal AIS genes. No AIS genes were identified in genome of the tunicate Ciona intestinalis, a urochordate representative (4, 5). In Amphioxus, which is a cephalochordate representative, secreted VCBP proteins consisting of two diverse V-type Igs and a chitin-binding domain were found (6), as well as molecules containing one V domain and a domain spanning the membrane five times (7), but these molecules are unlikely to be direct precursors of the vertebrate antigen-specific receptors. The first jawless fish appeared Ϸ550 million years ago (mya), and these early craniates diverged into two lineages. One lineage included the ancestors of hagfish and lamprey, and the other lineage included armored shell-skinned fish (Ostracoderms), which were ancestors of the j...

Reconstructing immune phylogeny: new perspectives

“…Accelerated allograft rejection has been documented in lampreys 84 , as have humoral responses to immunization with bacterial and cellular antigens; however, the circulating AGGLUTININS are not related structurally to antibodies 28 . Extensive EXPRESSED SEQUENCE TAG (EST) surveys have failed to identify typical lymphocyte-specific cell-surface determinants in lampreys 85,86 , with the exceptions of a predicted gene product that shows a distant relationship to CD4 (among other molecules) 87 and another monomorphic gene product that has cytosolic ITIMs and can be modelled to TCR V regions but shows only remote primary-structure similarity to jawed-vertebrate TCRs 87 . However, Ikaros and SPI, which are transcription factors that function in higher-vertebrate lymphocyte development and differentiation, have been identified in jawless vertebrates [88][89][90][91] , as have ETS-(M. Anderson, personal communication), GATA-binding protein 2 (GATA2)-and GATA3-type molecules (J.P.C.…”

An evolutionarily mobile antigen receptor variable region gene: Doubly rearranging NAR-TcR genes in sharks

“…2). It is peculiar that NAR-TcRV and IgNARV group not only outside of Ig and TcR V domains but also basal to diverse chordate V domains (30)(31)(32)(33)(34)(35). We hesitate to infer from the tree an ancestral relationship between the NAR-TcR and IgNAR domains and those of conventional Ig and TcR, despite the parsimony of a single binding domain and the position of the IgNARV͞ NAR-TcRV cluster, because establishing alignments of such diverse V domains is challenging.…”

Variable domains and a VpreB-like molecule are present in a jawless vertebrate

“…Although such short motifs are essentially ubiquitous among proteins, the Amptrap method filters only those cDNAs encoding secretion signal sequences and of a specified length from a given tissue. Of the two primary strategies employed here, the one directed at the highly conserved tryptophan residue in the V region has been the more productive (J. Cannon, unpublished observations) and provides one explanation (see below) for why a recently identified lamprey gene with certain TCRV features (Pancer et al 2004b) was not amplified as it lacks this residue.…”

“…The recent description of a non-rearranging single copy gene sequence in lamprey that can be modeled to a TCR V suggests that other molecules that are related to the combinatorial antigen binding receptors may exist in jawless vertebrates (Pancer et al 2004b). Further characterization of the PM3033 gene product, particularly its ontogenetic expression and association with other cell surface molecules, could address the possibility that a molecule that plays no direct role in antigen binding but has a significant place in B cell ontogeny arose independently from the antigen-binding receptors seen in contemporary jawed vertebrates.…”