Evolution of two distinct variable lymphocyte receptors in lampreys: VLRD and VLRE

Jawless vertebrates possess an alternative adaptive immune system in which antigens are recognized by variable lymphocyte receptors (VLRs) generated by combinatorial assembly of leucine-rich repeat (LRR) cassettes. Three types of receptors, VLRA, VLRB, and VLRC, have been previously identified. VLRA- and VLRC-expressing cells are T cell-like, whereas VLRB-expressing cells are B cell-like. Here, we report two types of VLRs in lampreys, VLRD and VLRE, phylogenetically related to VLRA and VLRC. The germline VLRD and VLRE genes are flanked by 39 LRR cassettes used in the assembly of mature VLRD and VLRE, with cassettes from chromosomes containing the VLRA and VLRC genes also contributing to VLRD and VLRE assemblies. VLRD and VLRE transcription is highest in the triple-negative (VLRA^-/VLRB^-/VLRC^-) population of lymphocytes, albeit also detectable in VLRA⁺ and VLRC⁺ populations. Tissue distribution studies suggest that lamprey VLRD⁺ and VLRE⁺ lymphocytes comprise T-like sublineages of cells.