Thereafter, activated helper T cells control production of antigen-specific antibodies from B cells [6]. Therefore, activation of innate immunity through PRRs is required for initiation of adaptive immunity mediated by T and B cells. Vertebrates are classified as jawed and jawless [7]. Because jawless vertebrates are the most primitive vertebrates, they have been studied to gain understanding of the evolutionary processes that gave

rise to the innate and adaptive immune systems in vertebrates ([8]–[10]). In this review, we will summarize the innate and adaptive immune systems of jawless vertebrates and the convergent evolution of these systems in vertebrates. Jawless vertebrates, including lampreys and hagfish, S1P Receptor inhibitor and jawed vertebrates are sister groups (Fig. 1). Molecular phylogenetic and paleontological studies indicate that these two groups of vertebrates diverged approximately 500 million years ago [7], [11]. Studies of jawless vertebrates have identified LLCs, which are morphologically similar to the T and B cells of jawed vertebrates [12]. Moreover, like jawed vertebrates, jawless vertebrates are capable of producing antigen-specific agglutinins and of forming immunological memory regarding rejection of skin allografts [13], [14]. These findings indicate that jawless vertebrates possess adaptive immunity that is similar to that of jawed vertebrates.

However, recent transcriptome analyses of LLCs have failed to identify important molecules that are central to the adaptive immunity buy LY2109761 of jawed Liothyronine Sodium vertebrates, such as the TCRs, BCRs, MHCs and RAGs (Fig. 1) [15], [16]. Hence, jawless vertebrates have a unique adaptive immune system that is not based on those molecules. Novel

rearranging antigen receptors, the VLRs, have been identified as the candidate molecules that mediate adaptive immune responses of jawless vertebrates [17]. In some mitogen- and antigen-stimulated sea lampreys, many VLR transcripts containing variable numbers of diverse LRRs can be identified in activated LLCs. VLRs encode a SP, an LRRNT, multiple LRRs, a CP, a LRRCT and an invariant stalk region (2a). Based on consensus motifs and length, the LRRs are classified according to the most N-terminal LRR1 (18 residues), the most C-terminal LRRVe (24 residues) and the LRRV (24 residues) that is located between the LRR1 and the LRRVe. In each VLR transcript, the sequence of each LRR module is distinct and the number of LRRV modules variable. Before somatic rearrangement, the gVLR gene is incapable of encoding a functional protein. Two VLR genes, designated VLRA and VLRB, have been identified in hagfish and lampreys [18], [19]. VLRB was first described in sea lampreys. In hagfish, the VLRA and VLRB loci are located far apart on the same chromosome [20]. Recently, a third VLR gene, termed VLRC, was identified in lampreys [21].