Immune related genes underpin the evolution of adaptive immunity in jawless vertebrates

Abstract

The study of immune related genes in lampreys and hagfish provides a unique perspective on the evolutionary genetic underpinnings of adaptive immunity and the evolution of vertebrate genomes. Separated from their jawed cousins at the stem of the vertebrate lineage, these jawless vertebrates have many of the gene families and gene regulatory networks associated with the defining morphological and physiological features of vertebrates. These include genes vital for innate immunity, inflammation, wound healing, protein degradation, and the development, signaling and trafficking of lymphocytes. Jawless vertebrates recognize antigen by using leucine-rich repeat (LRR) based variable lymphocyte receptors (VLRs), which are very different from the immunoglobulin (Ig) based T cell receptor (TCR) and B cell receptor (BCR) used for antigen recognition by jawed vertebrates. The somatically constructed VLR genes are expressed in monoallelic fashion by T-like and B-like lymphocytes. Jawless and jawed vertebrates thus share many of the genes that provide the molecular infrastructure and physiological context for adaptive immune responses, yet use entirely different genes and mechanisms of combinatorial assembly to generate diverse repertoires of antigen recognition receptors.

Keywords: Adaptive immunity; Antigen receptor; Evolution; Jawless vertebrate; Leucine-rich repeat; Phylogeny; Somatic diversification; Variable Lymphocyte Receptor..

Fig. (1). Adaptive immunity throughout vertebrate phylogeny.

Vertebrates employ an adaptive strategy for immune defense that relies upon several universal characteristics. Jawless (agnathan) and jawed (gnathostome) vertebrate lineages differ, however, in several fundamental elements of adaptive immunity. Agnathans recognize antigens with VLRs constructed of LRR modules; CDA1 and CDA2 have been posited as critical mediators of VLR somatic diversification. Gnathostomes construct Ig and TCR antigen receptors from IgSF domains; in this lineage RAG1 and RAG2 are vital for gene assembly and AID for somatic hypermutation, class switching, and gene conversion. Two whole-genome duplications have been proposed during vertebrate evolution (indicated by stars).

Fig. (2). Adaptive immunity in the context of conserved immune related genes.

The adaptive immune systems of jawless and jawed vertebrates differ fundamentally in the antigen receptors used and in the mechanisms for receptor diversification. In both lineages, however, common sets of immune related genes in different functional categories facilitate the development and operation of adaptive immunity.

Fig. (3). VLR gene assembly in lamprey lymphocytes.

The incomplete germline VLR genes are flanked by hundreds of LRR cassettes. The noncoding intervening sequence of germline VLR is replaced by LRR fragments that are sequentially copied from the flanking LRR cassettes. Mature complete VLR genes are assembled from either the LRRNT or LRRCT end in a stepwise fashion that is directed by short sequence homology between the donor and recipient LRR sequences. This figure was modified from [6].