Evolutionary implications of a third lymphocyte lineage in lampreys

Cells expressing variable lymphocyte receptor C ( VLRC ) genes that encode VLRC receptors, which are used by jawless vertebrates to react with antigens, are defined as a second T-cell-like lymphocyte subset (the first being VLRA-bearing cells); distinct properties of these two T-cell-like subsets are reminiscent of the distinction between αβ and γδ T cells in jawed vertebrates. A glimpse of ancient immune systems The jawless vertebrates have an adaptive immune system that uses somatically diversified leucine-rich repeat receptors (VLRs) to recognize antigens, rather than the T- and B-cell receptors of jawed vertebrates. However the VLRB- and VLRA-bearing cells have features that resemble B and T cells, respectively. This study defines a third lineage of lymphocytes in a jawless vertebrate — the lamprey — that expresses the recently described VLRC receptors. The differences between the lamprey's two T-cell-like lymphocyte subsets echo the distinction between the αβ and γδ T-cell lineages of jawed vertebrates, suggesting that functional specialization of distinct T-cell-like lineages was an ancient feature of a primordial immune system. Jawed vertebrates (gnathostomes) and jawless vertebrates (cyclostomes) have different adaptive immune systems 1 , 2 . Gnathostomes use T- and B-cell antigen receptors belonging to the immunoglobulin superfamily 3 , 4 . Cyclostomes, the lampreys and hagfish, instead use leucine-rich repeat proteins to construct variable lymphocyte receptors (VLRs), two types of which, VLRA and VLRB, are reciprocally expressed by lymphocytes resembling gnathostome T and B cells 5 , 6 , 7 . Here we define another lineage of T-cell-like lymphocytes that express the recently identified VLRC receptors 8 , 9 . Both VLRC + and VLRA + lymphocytes express orthologues of genes that gnathostome γδ and αβ T cells use for their differentiation, undergo VLRC and VLRA assembly and repertoire diversification in the ‘thymoid’ gill region, and express their VLRs solely as cell-surface proteins. Our findings suggest that the genetic programmes for two primordial T-cell lineages and a prototypic B-cell lineage were already present in the last common vertebrate ancestor approximately 500 million years ago. We propose that functional specialization of distinct T-cell-like lineages was an ancient feature of a primordial immune system.