Variable lymphocyte receptor F is generated via somatic diversification and expressed by lamprey T-like cells

Sabyasachi Das (), Francisco Fontenla-Iglesias, Masayuki Hirano, Ryo Morimoto, Byron B. Au-Yeung, Yashuo Wang, Weiming Li, Thomas Boehm, Jonathan P. Rast () and Max D. Cooper ()
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Sabyasachi Das: Emory University
Francisco Fontenla-Iglesias: Emory University
Masayuki Hirano: Emory University
Ryo Morimoto: Max-Planck Institute of Immunobiology and Epigenetics
Byron B. Au-Yeung: Lowance Center for Human Immunology
Yashuo Wang: Emory University
Weiming Li: Michigan State University
Thomas Boehm: Max-Planck Institute of Immunobiology and Epigenetics
Jonathan P. Rast: Emory University
Max D. Cooper: Emory University

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract All extant jawless vertebrates (lampreys and hagfishes) possess a unique adaptive immune system characterized by highly variable lymphocyte receptors (VLR) that are assembled in developing lymphocytes using leucine-rich-repeat donor cassettes. Five VLR types have been identified in lampreys: VLRA, VLRB, VLRC, VLRD, and VLRE. VLRB-expressing lymphocytes are functional analogs to B cells, whereas VLRA, VLRC, VLRD, and VLRE-expressing lymphocytes are more akin to T cells of jawed vertebrates. Here we define an additional VLR, designated VLRF. VLRF is phylogenetically closest to VLRA, with which it likely shares a common ancestral gene of at least 250 million years in the past. VLR assembly analyses show that VLRA, VLRC, VLRD, VLRE, and VLRF share donor cassettes through long-range intra- and inter-chromosomal interactions, whereas VLRB utilizes a distinct, dedicated cassette set. The pattern of gene expression, donor cassette usage, and distinctive amino acid composition in the C-terminal stalk suggest that VLRF⁺ lymphocytes may represent an additional T-like sub-lineage, adding further complexity to the VLR-based adaptive immune system.

Date: 2025
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DOI: 10.1038/s41467-025-61187-1

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