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The lamprey’s alternative immune system

The sea lamprey

The sea lamprey draws attention mainly for its alienlike appearance, particularly its oval mouth ringed with rows of sharp teeth that allow the parasitic creature to latch onto a fish host. These eel-like creatures are often called “living fossils” because they are thought to have changed little since they arose 450 million to 500 million years ago, as part of a branch of jawless creatures that split off early from the rest of the vertebrate tree. Lampreys and hagfish are the only survivors of that jawless branch, and accumulating evidence indicates that the animals have developed an immune system far different from that of other vertebrates, including people. Today, in Nature, a team led by Max Cooper of Emory University in Atlanta, Georgia, unveils the latest chapter in this emerging evolutionary tale, providing data indicating that the sea lamprey has its own versions of B and T cells, the two cell types central to the so-called adaptive immune response found in people. Whether those lamprey cells are related to our T and B cells, or are an independent invention, remains unclear, but that hasn’t dampened the fascination of immunologists. “I don’t think there’s any question now that there’s a separate adaptive immune system in the lampreys,” says Chris Amemiya of the Benaroya Research Institute at Virginia Mason in Seattle, Washington.

This month’s Origins essay tackled the evolution of the immune system, but it took a decidedly parochial view of the topic, focusing primarily on the microbial defenses wielded by people and other jawed vertebrates. The essay didn’t describe the lamprey story, which first gained prominence several years ago.

At that time, many biologists examining the evolution of animal immunity had largely focused on what is called the “big bang of immunology.” It was known that vertebrates and invertebrates share an initial immune response, dubbed innate immunity, that attacks microbes in a relatively nonspecific way, using inflammatory molecules and cells such as macrophages. But it has long been thought that only jawed vertebrates have the adaptive immune arm, which homes in on specific features of a microbe with exquisitely tailored antibodies, made by B cells, and related receptors on the surfaces of T cells. This split led many investigators to explore how the highly diverse antibodies and T cell receptors arose. Studies slowly revealed that perhaps 450 million years ago, an early ancestor of jawed vertebrates somehow obtained two genes, RAG1 and RAG2, that enabled its immune cells to scramble gene segments called V, D, and J to produce millions of distinct pathogen-recognizing proteins.

The jawless vertebrates missed out on this immunological explosion, it seemed—they don’t possess RAG1 and RAG2 and don’t make traditional antibodies or T cell receptors. Yet there were signs that the lamprey responds to immune challenges in much the same way that other vertebrates do. Then, in 2004, Cooper, Amemiya, and others reported the discovery of apparent pathogen-receptor molecules made by lamprey immune cells. These proteins were dubbed variable lymphocyte receptors (VLRs) because they, like antibodies and T cell receptors, come in millions of subtly diverse forms. But rather than relying on RAG1 and RAG2 to shuffle V, D, and J gene segments, the lamprey somehow stitches together other types of gene segments, ones encoding bits of protein rich in leucine amino acids.

Since then, Cooper and others have been piecing together the molecular details of the lamprey immune system and speculating about its origins. And they have found striking parallels to T and B cells. Lampreys have two genes, VLRA and VLRB, for their microbial receptors, and the latest studies show that different cell populations use one or the other, not both. The lamprey cells expressing VLRB act a lot like human B cells. They can use their VLR to attach to bacterial molecules and then transform into cells that secrete free VLRs that can bind to microbes and presumably promote their clearance, much as B cells become plasma cells that spit out pathogen-fighting antibodies. In the new Nature paper, Cooper’s group takes a closer look at the lamprey immune cells using the VLRA gene and finds that  they resemble T cells. The VLRA receptors remain bound to the cell’s surface, unlike the secreted molecules made by the VLRBs. Moreover, when they recognize a target, these VLRA cells make some of the same pro-inflammatory chemicals as T cells. Indeed, when the researchers compared the distinctive genetic activity of VLRA and VLRB cells, the activated genes resemble those of T and B cells, respectively.

Does that mean that VLR- and VDJ-based systems have a common evolutionary origin? Or is it a case of convergent evolution, in which the jawed and jawless vertebrates independently hit upon similar solutions to similar problems? Amemiya believes that it’s premature to decide between these options. But either way the finding is important, immunologists say. “Before the isolation of VLRs, the field suffered from having to theorize from a single example of adaptive system. It was a lot like astrobiology in this sense,” comments immunologist Jonathan Rast of the University of Toronto in Canada. “Now there are likely two acquired immune systems [VDJ- and VLR-mediated], and the real question is to what extent they are evolutionarily independent. Either way, the findings described in the Nature paper are very exciting. If the VLRA- and VLRB-bearing cells share some type of true homology with T and B cells, respectively, then a whole set of evolutionary questions arises as to how completely different diversifying receptor proteins were inserted into the jawed and jawless systems. If they are convergent with respect to their cell-bound and secretory cell types, which seems the most likely alternative at present, then a general principle about the constraints under which these systems evolve may emerge.”

In their paper, Cooper and his colleagues outline a number of unresolved issues surrounding the lamprey immune system, including the details of how the fish rearranges its DNA to make the VLR receptors. Another is the apparent lack of a thymus in the lamprey. In jawed vertebrates, this is where an animal’s T cells go to learn not to attack its own tissues. Given the diversity of VLRs a lamprey can apparently generate, it must also have a way of ignoring, ones that recognize its own tissues. This ability to distinguish between self and nonself is fundamental to our health—when that skill falters in people, autoimmune diseases result—but it’s not clear how lampreys accomplish the same feat without a thymus. “The new data in lampreys, together with earlier observations in urochordates [invertebrates such as sea squirts], clearly demonstrate that unique and specialized self-discrimination systems have evolved independently in different animal groups,” says Thomas C. G. Bosch of Christian Albrechts University Kiel in Germany, who studies the evolution of immunity in invertebrates.

And to Bosch, the lamprey story demystifies to some extent the big bang of immunology, indicating that adaptive immunity didn’t appear all at once, even if new microbial receptor systems occasionally showed up fast. “The sudden origin of adaptive immunity in vertebrates … is nothing but the appearance of an effective molecular recognition system involving taxonomically restricted genes,” he argues.

Amemiya notes that lampreys may not be the only ones with an adaptive immune arm distinct from that in jawed vertebrates. He cites evidence that snails and amphioxus, which split off from vertebrates even before lampreys, have something similar. “This may be the tip of the iceberg,” says Amemiya.