Déjà vu: the identity of a third lineage of lymphocytes in lampreys

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Unlike jawed vertebrates that recognize antigen by T-cell and B-cell receptors, jawless vertebrates represented by hagfish and lampreys use variable lymphocyte receptors (VLRs) as antigen receptors.1 The discovery of a VLR gene, which generates diversity by somatically assembling variable leucine-rich repeat (LRR) modules and whose product is expressed clonally on lymphocytes, demonstrated that jawless vertebrates had developed a unique adaptive immune system, thus highlighting the existence of two distinct forms of adaptive immunity in vertebrates.2 However, subsequent work has shown that their adaptive immune systems also have much in common. Particularly, remarkable is that lampreys have two populations of lymphocytes expressing distinct type of VLRs, named VLRA and VLRB, resembling T cells and B cells of jawed vertebrates, respectively.3 When a third VLR, named VLRC, was identified and found to be expressed on a population of lymphocytes expressing neither VLRA nor VLRB, the nature of this population became the focus of interest.4 In a recent paper published in Nature, Hirano and his colleagues5 demonstrate that VLRC+ cells are T-cell-like and suggest that they might be akin to γδ T cells. Thus, similar to jawed vertebrates equipped with B cells, αβ T cells and γδ T cells, lampreys have one B-cell-like lineage and two T-cell-like lineages, providing yet another piece of evidence supporting the similarity of the two forms of adaptive immune systems.