A structural basis for antigen recognition by the T cell-like lymphocytes of sea lamprey

Adaptive immunity in jawless vertebrates is mediated by leucine-rich repeat proteins called variable lymphocyte receptors (VLRs). Two types of VLR (A and B) are expressed by mutually exclusive lymphocyte populations in lamprey. VLRB lymphocytes resemble the B cells of jawed vertebrates; VLRA lymphocytes are similar to T cells. We determined the structure of a high-affinity VLRA isolated from lamprey immunized with hen egg white lysozyme (HEL) in unbound and antigen-bound forms. The VLRA-HEL complex demonstrates that certain VLRAs, like gamma delta T-cell receptors (TCRs) but unlike alpha beta TCRs, can recognize antigens directly, without a requirement for processing orantigen-presenting molecules. Thus, these VLRAs feature the nanomolar affinities of antibodies, the direct recognition of unprocessed antigens of both antibodies and gamma delta TCRs, and the exclusive expression on the lymphocyte surface that is unique to alpha beta and gamma delta TCRs.