Assistant Professor Emory University School of Medicine Atlanta, Georgia, United States
Disclosure(s):
Sabyasachi Das, PhD: No financial relationships to disclose
Introduction/Rationale: Understanding the evolution of vertebrate adaptive immunity requires comparative analyses of anticipatory antigen receptors. Jawed vertebrates (gnathostomes) use immunoglobulin-based receptors generated by V(D)J recombination, whereas jawless vertebrates (agnathans), lampreys and hagfish, use variable lymphocyte receptors (VLRs) assembled from leucine-rich repeat (LRR) cassettes. Canonical germline VLR genes are incomplete, encoding invariant N- and C-terminal regions separated by noncoding intervening segments, and the evolutionary origin of this anticipatory system remains unresolved.
Methods: We analyzed lamprey and hagfish genomes to identify intact VLR-like genes and characterized their genomic context and phylogenetic relationships. Single-cell transcriptomics and quantitative PCR were used to define cell-type and tissue expression patterns. Structural modelling was used to predict the overall fold, LRR composition, and C-terminal stalk features of the encoded receptor.
Results: We discovered a primordial VLR-like gene (priVLR) in both lampreys and hagfish. Structural models indicate that the translated priVLR sequence adopts the characteristic VLR solenoid architecture with an extended LRRCT loop. Unlike canonical germline VLR loci, priVLR lacks noncoding intervening segments. Similar to VLRB, priVLR possess a predicted GPI-cleavage site in its C-terminal stalk and clusters phylogenetically with VLRB. However, single-cell transcriptomic analyses show that, in contrast to VLRB expression in B-like cells, priVLR is predominantly expressed in T-like lymphocyte populations in both species.
Conclusion: Characteristics of priVLR suggest that it may derive from an ancestral intact LRR genes that later gave rise to the more complex diversifying VLR isotypes that underpin antigen recognition in agnathans. Understanding the function of the priVLR protein in agnathan T-like lymphocytes has the potential to provide new insight into the origin of the agnathan adaptive immune system.
